Document:

<PAGE>

                                                                   EXHIBIT 10.22

THESE SECURITIES HAVE NOT BEEN REGISTERED UNDER THE SECURITIES ACTTHESE
SECURITIES HAVE NOT BEEN REGISTERED UNDER THE SECURITIES ACT OF 1933, AS AMENDED
FROM TIME TO TIME (THE "1933 ACT"). THEY MAY NOT BE SOLD, OFFERED FOR SALE,
PLEDGED, OR HYPOTHECATED IN THE ABSENCE OF AN EFFECTIVE REGISTRATION STATEMENT
RELATED THERETO OR AN OPINION OF COUNSEL (WHICH MAY BE COMPANY COUNSEL)
REASONABLY SATISFACTORY TO THE COMPANY THAT SUCH REGISTRATION IS NOT REQUIRED
UNDER THE 1933 ACT OR IN COMPLIANCE WITH RULE 144 UNDER THE 1933 ACT.

                               WARRANT AGREEMENT

                   To Purchase Shares of the Common Stock of

                         INSPIRE PHARMACEUTICALS, INC.

             Dated as of December 17, 1999 (the "Effective Date")

     WHEREAS, Inspire Pharmaceuticals, Inc., a Delaware corporation (the
"Company") has entered into a Series G Preferred Stock and Warrant Purchase
Agreement dated as of December 17, 1999 (the "Agreement"), with Genentech, Inc.,
a Delaware corporation, or its successors or assigns (the "Warrantholder"); and

     WHEREAS, pursuant to the terms of the Agreement, the Company is required to
grant to Warrantholder the right to purchase certain shares of its Common Stock
(the "Warrant");

     NOW, THEREFORE, in consideration of mutual covenants and agreements
contained herein, the Company and Warrantholder agree as follows:

1.   GRANT OF THE RIGHT TO PURCHASE COMMON STOCK.
     -------------------------------------------

     The Company hereby grants to the Warrantholder, and the Warrantholder is
entitled, upon the terms and subject to the conditions set forth in this Warrant
Agreement, to subscribe to and purchase, from the Company, 444,444 fully paid
and non-assessable shares of the Company's Common Stock ("Common Stock") at a
purchase price of $4.50 per share (the "Exercise Price"). The number and
purchase price of such shares are subject to adjustment as provided in Section
8.

2.   TERM OF THE WARRANT AGREEMENT.
     -----------------------------

     Except as otherwise provided for in this Warrant Agreement, the term of
this Warrant Agreement and the right to purchase Common Stock as granted in this
Warrant Agreement shall commence on the Effective Date and shall be exercisable
for a period of five (5) years.

3.   EXERCISE OF THE PURCHASE RIGHTS.
     -------------------------------

     (a)  Exercise.  The purchase rights set forth in this Warrant Agreement are
exercisable by the Warrantholder, in whole or in part, at any time, or from time
to time, prior to the expiration of the term set forth in Section 2, by
tendering to the Company at its principal office a notice of exercise in the
form attached hereto as Exhibit I (the "Notice of Exercise"), duly completed and
executed. Promptly upon receipt of the Notice of Exercise, the payment of the
purchase price in accordance with the terms set
<PAGE>

forth below and execution of the Agreement to be Bound as provided in Section
3(c), and in no event later than ten (10) business days thereafter, the Company
shall issue to the Warrantholder a certificate for the number of shares of
Common Stock purchased and shall execute the Notice of Exercise indicating the
number of shares which remain subject to future purchases, if any.

     (b)  Payment of Exercise Price.  The Exercise Price may be paid at the
Warrantholder's election either (i) by cash or check, or (ii) by surrender of
Warrants ("Net Issuance") as determined below.  If the Warrantholder elects the
Net Issuance method, the Company will issue Common Stock in accordance with the
following formula:

                                  X =  Y(A-B)
                                       ------
                                         A

Where:X = the number of shares of Common Stock to be issued to the
          Warrantholder.

          Y =    the number of shares of Common Stock requested to be
                 exercised under this Warrant Agreement.

          A =    the fair market value of one (1) share of Common Stock.

          B =    the Exercise Price.

     As used in this Section 2, current fair market value of Common Stock shall
mean with respect to each share of Common Stock:

          (i)    if the exercise is in connection with an initial public
offering, and if the Company's Registration Statement relating to such public
offering has been declared effective by the SEC, then the initial "Price to
Public" specified in the final prospectus with respect to the offering;

          (ii)   if this Warrant is exercised after, and not in connection
with, the Company's initial public offering, and:

                 (A)  if traded on a securities exchange or the Nasdaq National
Market System ("NASDAQ SYSTEM"), the fair market value shall be deemed to be the
average of the closing or last reported sale prices on such exchange or market
over a twenty-one (21) day period ending three days before the day the current
fair market value of the securities is being determined; or

                 (B)  if actively traded over-the-counter, the fair market value
shall be deemed to be the average of the closing bid and asked prices quoted on
the NASDAQ System (or similar system) over the twenty-one (21) day period ending
three days before the day the current fair market value of the securities is
being determined;

          (iii)  if at any time the Common Stock is not listed on any securities
exchange or quoted in the NASDAQ System or the over-the-counter market, the
current fair market value of Common Stock shall be the highest price per share
which the Company could obtain from a willing buyer (not a current employee or
director) for shares of Common Stock sold by the Company, from authorized but
unissued shares, as determined in good faith by its Board of Directors, unless
the Company shall become subject to a merger, acquisition or other consolidation
pursuant to which the Company is not the surviving party, in which case the fair
market value of Common Stock shall be

                                       2
<PAGE>

deemed to be the value received by the holders of the Company's Common Stock on
a common equivalent basis pursuant to such merger or acquisition.

     (c)  Agreement to be Bound to Stockholders' Agreement and Investors' Rights
Agreement. It shall be a condition to the Warrantholder's right to purchase
shares under this Warrant Agreement that the Warrantholder shall have executed
and delivered to the Company a counterpart of the Second Amended and Restated
Stockholders Agreement among the Company and certain of its stockholders dated
April 8, 1997, as amended (the "Stockholders' Agreement") pursuant to which the
Warrantholder shall be subject to all provisions therein applicable to holders
of Common Stock of the Company except Section 4 thereof relating to rights of
first refusal and co-sale, and a counterpart of the Investors' Rights Agreement,
as amended, among the Company and certain of its preferred stockholders dated
October 29, 1999 (the "Investors' Rights Agreement") pursuant to which the
Warrantholder shall be subject to all provisions therein applicable to holders
of Registrable Securities (as defined therein) that convert from the Series G
Stock.

     (d)  Reissue of Warrant After Partial Exercise. Upon partial exercise by
either cash or Net Issuance, the Company shall promptly issue an amended Warrant
Agreement representing the remaining number of shares purchasable hereunder. All
other terms and conditions of such amended Warrant Agreement shall be identical
to those contained herein, including, but not limited to the Effective Date
hereof.

4.   RESERVATION OF SHARES.
     ---------------------

     (a)  Authorization and Reservation of Shares.  During the term of this
Warrant Agreement, the Company will at all times have authorized and reserved a
sufficient number of shares of its Common Stock to provide for the exercise of
the rights to purchase Common Stock as provided for in this Warrant Agreement.

     (b)  Registration or Listing.  If any shares of Common Stock required to be
reserved hereunder require registration with or approval of any governmental
authority under any Federal or state law (other than any registration under the
1933 Act, as then in effect, or any similar Federal statute then enforced, or
any state securities law, required by reason of any transfer involved in such
conversion), or listing on any domestic securities exchange, before such shares
may be issued upon exercise, the Company will, at its expense and as
expeditiously as possible, use its best efforts to cause such shares to be duly
registered, listed or approved for listing on such domestic securities exchange,
as the case may be.

5.   NO FRACTIONAL SHARES OR SCRIP.
     -----------------------------

     No fractional shares or scrip representing fractional shares shall be
issued upon the exercise of this Warrant, but in lieu of such fractional shares
the Company shall make a cash payment therefor upon the basis of the Exercise
Price then in effect.

6.   NO RIGHTS AS SHAREHOLDER.
     ------------------------

     This Warrant Agreement does not entitle the Warrantholder to any voting
rights or other rights as a shareholder of the Company prior to the exercise of
the Warrant.

                                       3
<PAGE>

7.   WARRANTHOLDER REGISTRY.
     ----------------------

     The Company shall maintain a registry showing the name and address of the
registered holder of this Warrant Agreement.

8.   ADJUSTMENT RIGHTS.
     -----------------

     The purchase price per share and the number of shares of Common Stock
purchasable hereunder are subject to adjustment, as follows:

     (a)  Merger and Sale of Assets.  If at any time there shall be a capital
reorganization of the shares of the Company's Common Stock (other than a
combination, reclassification, exchange or subdivision of shares otherwise
provided for herein), or a merger or consolidation of the Company with or into
another corporation when the Company is not the surviving corporation, or the
sale of all or substantially all of the Company's properties and assets to any
other person (hereinafter referred to as a "Merger Event"), then, as part of
such Merger Event, lawful provision shall be made so that the Warrantholder
shall thereafter be entitled to receive, upon exercise of the Warrant, the
number of shares of Common Stock or other securities of the successor
corporation resulting from such Merger Event, equivalent in value to that which
would have been issuable if Warrantholder had exercised this Warrant immediately
prior to the Merger Event. In any such case, appropriate adjustment (as
determined in good faith by the Company's Board of Directors) shall be made in
the application of the provisions of this Warrant Agreement with respect to the
rights and interest of the Warrantholder after the Merger Event to the end that
the provisions of this Warrant Agreement (including adjustments of the Exercise
Price and number of shares of Common Stock purchasable) shall be applicable to
the greatest extent possible.

     (b)  Reclassification of Shares.  If the Company at any time shall, by
combination, reclassification, exchange or subdivision of securities or
otherwise, change any of the securities as to which purchase rights under this
Warrant Agreement exist into the same or a different number of securities of any
other class or classes, this Warrant Agreement shall thereafter represent the
right to acquire such number and kind of securities as would have been issuable
as the result of such change with respect to the securities which were subject
to the purchase rights under this Warrant Agreement immediately prior to such
combination, reclassification, exchange, subdivision or other change.

     (c)  Subdivision or Combination of Shares.  If the Company at any time
shall combine or subdivide its Common Stock, the Exercise Price and number of
shares subject to purchase hereunder shall be proportionately decreased in the
case of a subdivision, or proportionately increased in the case of a
combination. Any adjustment under this Section 8(c) shall become effective at
the close of business on the date the subdivision or combination becomes
effective.

     (d)  Stock Dividends.  If the Company at any time shall pay a dividend
payable in, or make any other distribution of capital stock (except any
distribution specifically provided for in the foregoing subsections (a) or (b))
on the Company's Common Stock, then the Exercise Price shall be adjusted, from
and after the record date of such dividend or distribution, to that price
determined by multiplying the Exercise Price in effect immediately prior to such
record date by a fraction (i) the numerator of which shall be the total number
of all shares of the Company's Common Stock outstanding immediately prior to
such dividend or distribution, and (ii) the denominator of which shall be the
total number of all shares of the Company's Common Stock outstanding immediately
after such dividend or distribution.  The Warrantholder shall thereafter be
entitled to purchase, at the Exercise Price resulting from such adjustment, the
number of shares of Common Stock  (calculated to the nearest whole share)
obtained by

                                       4
<PAGE>

multiplying the Exercise Price in effect immediately prior to such adjustment by
the number of shares of Common Stock subject to this Warrant immediately prior
to such adjustment and dividing the product thereof by the Exercise Price
resulting from such adjustment. Any adjustment under this Section 8(d) shall
become effective at the close of business on the record date of such dividend,
or in the event that no record date is fixed, upon the making of such dividend.

     (e)  Notice of Adjustments.  If: (i) the Company shall declare any dividend
or distribution upon its stock, whether in cash, property, stock or other
securities; (ii) there shall be any Merger Event; or (iii) there shall be any
voluntary or involuntary dissolution, liquidation or winding up of the Company;
then, in connection with each such event, the Company shall send to the
Warrantholder: (A) at least twenty (20) days' prior written notice of the date
on which the books of the Company shall close or a record shall be taken for
such dividend, distribution, subscription rights (specifying the date on which
the holders of Common Stock shall be entitled thereto) or for determining rights
to vote in respect of such Merger Event, dissolution, liquidation or winding up;
and (B) in the case of any such Merger Event, dissolution, liquidation or
winding up, at least twenty (20) days' prior written notice of the date when the
same shall take place (and specifying the date on which the holders of Common
Stock shall be entitled to exchange their Common Stock for securities or other
property deliverable upon such Merger Event, dissolution, liquidation or winding
up). In the case of a public offering, the Company shall give Warrantholder at
least twenty (20) days' written notice prior to the effective date of such
offering.

     Each such written notice shall set forth, in reasonable detail: (i) the
event requiring the adjustment, (ii) the amount of the adjustment, (iii) the
method by which such adjustment was calculated, (iv) the Exercise Price, and (v)
the number of shares subject to purchase hereunder after giving effect to such
adjustment, and shall be given by first class mail, postage prepaid, addressed
to the Warrantholder, at the address as shown on the books of the Company.

     (f)  Timely Notice.  Failure to timely provide such notice required by
Section 8(e) shall entitle Warrantholder to retain the benefit of the applicable
notice period notwithstanding anything to the contrary contained in any
insufficient notice received by Warrantholder.  The notice period shall begin on
the date Warrantholder actually receives a written notice containing all the
information specified above.

9.   MISCELLANEOUS.
     -------------

     (a)  Assignment; Binding Effect.

          (i)    This Warrant Agreement and all rights hereunder are
transferable in whole or in part by the Warrantholder to any person or entity
upon written notice to the Company. The transfer shall be recorded on the books
of the Company upon the surrender of this Warrant Agreement, with the Transfer
Notice attached as Exhibit III hereto duly executed, to the Company at its
principal offices. In the event of a partial transfer, the Company shall issue
to the Warrantholders one or more appropriate new Warrant Agreements.

          (ii)   Except as otherwise provided herein, the terms and conditions
of this Warrant Agreement shall inure to the benefit of and be binding upon the
respective successors and permitted assigns of the parties (including
transferees of the warrant). Nothing in this Warrant Agreement, express or
implied, is intended to confer upon any party other than the parties hereto or
their respective

                                       5
<PAGE>

successors and permitted assigns any rights, remedies, obligations, or
liabilities under or by reason of this Warrant Agreement, except as expressly
provided in this Warrant Agreement.

          (b)  Governing Law.   This Warrant Agreement shall be governed by and
construed in accordance with the laws of the State of Delaware without regard to
principles of conflicts of law.

          (c)  Counterparts.  This Warrant Agreement may be executed in two or
more counterparts, each of which shall be deemed an original, but all of which
together shall constitute one and the same instrument.

          (d)  Captions.  The captions used in this Warrant Agreement are for
convenience only and are not to be considered in construing or interpreting this
Warrant Agreement.

          (e)  Notices.   Any notice or request required or permitted to be
given under or in connection with this Warrant Agreement shall be deemed to have
been sufficiently given if in writing and personally delivered or sent by
certified mail (return receipt requested), facsimile transmission (receipt
verified), or overnight express courier service (signature required), prepaid,
to the party for which such notice is intended, at the address set forth for
such party below:

               (i)    In the case of the Company, to:

                      Inspire Pharmaceuticals, Inc.
                      4222 Emperor Boulevard, Suite 470
                      Durham, North Carolina 27703
                      Attention: Christy L. Shaffer, Ph.D.
                      Facsimile No.: (919) 941-9797

               (ii)   In the case of the Warrantholder, to:

                      Genentech, Inc.
                      1 DNA Way, Mailstop 49
                      South San Francisco, California 94080
                      Attention: Corporate Secretary
                      Facsimile No.: (650) 952-9881

or to such other address for such party as it shall have specified by like
notice to the other party, provided that notices of a change of address shall be
effective only upon receipt thereof. If delivered personally or by facsimile
transmission, the date of delivery shall be deemed to be the date on which such
notice or request was given. If sent by overnight express courier service, the
date of delivery shall be deemed to be the next business day after such notice
or request was deposited with such service. If sent by certified mail, the date
of delivery shall be deemed to be the fifth business day after such notice or
request was deposited with the U.S. Postal Service.

     (f)  Remedies.  In the event of any default under this Warrant Agreement,
the non-defaulting party may proceed to protect and enforce its rights either by
suit in equity and/or by action at law, including but not limited to an action
for damages as a result of any such default, and/or an action for specific
performance for any default where Warrantholder will not have an adequate remedy
at law and where damages will not be readily ascertainable. The Company
expressly agrees that it shall not oppose an application by the Warrantholder or
any other person entitled to the benefit of this Warrant Agreement

                                       6
<PAGE>

requiring specific performance of any or all provisions hereof or enjoining the
Company from continuing to commit any such breach of this Warrant Agreement.

     (g)  No Impairment of Rights.  The Company will not, by amendment of its
Certificate of Incorporation or through any other means, avoid or seek to avoid
the observance or performance of any of the terms of this Warrant Agreement, but
will at all times in good faith assist in the carrying out of all such terms and
in the taking of all such actions as may be necessary or appropriate in order to
protect the rights of the Warrantholder against impairment.

     (h)  Amendments and Waivers.  Except as otherwise expressly set forth in
this Warrant Agreement, any term of this Warrant Agreement may be amended and
the observance of any term of this Warrant Agreement may be waived (either
generally or in a particular instance and either retroactively or
prospectively), with the written consent of the Company and the Warrantholder.
No waivers of or exceptions to any term, condition or provision of this Warrant
Agreement, in any one or more instances, shall be deemed to be, or construed as,
a further or continuing waiver of any such term, condition or provision.

     (i)  Severability.  If one or more provisions of this Warrant Agreement are
held to be unenforceable under applicable law, such provision shall be excluded
from this Warrant Agreement and the balance of the Warrant Agreement shall be
interpreted as if such provision were so excluded and shall be enforceable in
accordance with its terms.

     (j)  Entire Agreement.  This Warrant Agreement and the documents referred
to herein constitute the entire agreement among the parties and no party shall
be liable or bound to any other party in any manner by any warranties,
representations or covenants except as specifically set forth herein or therein.

                                     * * *

                                       7
<PAGE>

     IN WITNESS WHEREOF, the parties hereto have caused this Warrant Agreement
to be executed by its officers thereunto duly authorized as of the Effective
Date.

                              Company:  INSPIRE PHARMACEUTICALS, INC.

                              By:   /s/ Christy L. Shaffer
                                  -----------------------------------

                              Name:   Christy L. Shaffer, Ph.D.
                                    ----------------------------------

                              Title:  President and CEO
                                     ---------------------------------

                              Warrantholder: GENENTECH, INC.

                              By:   /s/ Arthur D. Levinson
                                  ------------------------------------

                              Name: Arthur D. Levinson, Ph.D.

                              Title: President and Chairman of the Board

                                       8
<PAGE>

                                   EXHIBIT I

                              NOTICE OF EXERCISE

To:  Inspire Pharmaceuticals, Inc.:

(1)  The undersigned Warrantholder hereby elects to purchase _____ shares of the
     Common Stock of Inspire Pharmaceuticals, Inc. pursuant to the terms of the
     Warrant Agreement dated December 17, 1999 (the "Warrant Agreement") between
     Inspire Pharmaceuticals, Inc. and the Warrantholder, and tenders herewith
     payment of the purchase price for such shares in full, together with all
     applicable transfer taxes, if any.

(2)  In connection with the exercise of its rights to purchase the Common Stock
     of Inspire Pharmaceuticals, Inc., the undersigned hereby makes the
     following representations and warranties:

     (a)  Investment Purpose.  The right to acquire Common Stock or the Common
          Stock issuable upon exercise of the Warrantholder's rights contained
          in the Warrant Agreement will be acquired for investment and not with
          a view to the sale or distribution of any part thereof, and the
          Warrantholder has no present intention of selling or engaging in any
          public distribution of the same except pursuant to a registration or
          exemption.

     (b)  Private Issue.  The Warrantholder understands (i) that the Common
          Stock issuable upon exercise of this Warrant is not registered under
          the 1933 Act or qualified under applicable state securities laws on
          the ground that the issuance contemplated by this Warrant Agreement
          will be exempt from the registration and qualifications requirements
          thereof, and (ii) that the Company's reliance on such exemption is
          predicated on the representations set forth in this Section.

     (c)  Disposition of Warrantholder's Rights.  In no event will the
          Warrantholder make a disposition of any of its rights to acquire
          Common Stock or Common Stock issuable upon exercise of such rights
          unless and until (i) it shall have notified the Company of the
          proposed disposition, and (ii) if requested by the Company, it shall
          have furnished the Company with an opinion of counsel (which counsel
          may either be inside or outside counsel to the Warrantholder)
          satisfactory to the Company and its counsel to the effect that (A)
          appropriate action necessary for compliance with the 1933 Act has been
          taken, or (B) an exemption from the registration requirements of the
          1933 Act has been taken, or (B) an exemption from the registration
          requirements of the 1933 Act is available. The Company agrees that an
          opinion of counsel will not be required for sales made in accordance
          with Rule 144, except in unusual circumstances. Notwithstanding the
          foregoing, the restrictions imposed upon the transferability of any of
          its rights to acquire Common Stock or Common Stock issuable on the
          exercise of such rights do not apply to transfers from the beneficial
          owner of any of the aforementioned securities to its nominee or from
          such nominee to its beneficial owner, and shall terminate as to any
          particular share of Common Stock when (1) such security shall have
          been effectively registered under the 1933 Act and sold by the holder
          thereof in accordance with such registration or (2) such security
          shall have been sold without registration in compliance with Rule 144
          under the 1933 Act, or (3) a letter shall have been issued to the
          Warrantholder at its request by the staff of the Securities and
          Exchange Commission or a

                                       9
<PAGE>

          ruling shall have been issued to the Warrantholders at its request by
          such Commission stating that no action shall be recommended by such
          staff or taken by such Commission, as the case may be, if such
          security is transferred without registration under the 1933 Act in
          accordance with the conditions set forth in such letter or ruling and
          such letter or ruling specifies that no subsequent restrictions on
          transfer are required. Whenever the restrictions imposed hereunder
          shall terminate, as provided in this Section, the Warrantholder or
          holder of a share of Common Stock then outstanding as to which such
          restrictions have terminated shall be entitled to receive from the
          Company, without expense to such holder, one or more new certificates
          for the Warrant or for such shares of Common Stock not bearing any
          restrictive legend.

     (d)  Financial Risk.  The Warrantholder has such knowledge and experience
          in financial and business matters as to be capable of evaluating the
          merits and risks of its investment, and has the ability to bear the
          economic risks of its investment.

     (e)  Risk of No Registration.  The Warrantholder understands that if the
          Company does not register with the Securities and Exchange Commission
          pursuant to Section 12 of the 1933 Act, or file reports pursuant to
          Section 15(d) of the Securities Exchange Act of 1934, as amended from
          time to time, or if a registration statement covering the securities
          under the 1933 Act is not in effect when it desires to sell (i) the
          rights to purchase Common Stock pursuant to this Warrant Agreement, or
          (ii) the Common Stock issuable upon exercise of the right to purchase,
          it may be required to hold such securities for an indefinite period.
          The Warrantholder also understands that any sale of its rights of the
          Warrantholder to purchase Common Stock in reliance upon Rule 144 under
          the 1933 Act may be made only in accordance with the terms and
          conditions of that Rule.

(3)  Please issue a certificate or certificates representing said shares of
     Common Stock in the name of the undersigned or in such other name as is
     specified below.

               Name:________________________________________

               Address: ____________________________________

               _____________________________________________

                         Warrantholder: GENENTECH, INC.

                         By: _____________________________________________

                         Name: ___________________________________________

                         Title: __________________________________________

                         Date: ___________________________________________

                                       10
<PAGE>

                                  EXHIBIT II

                          ACKNOWLEDGMENT OF EXERCISE

     The undersigned ________, _________, hereby acknowledge receipt of the
"Notice of Exercise" from to purchase _____ shares of the Common Stock of
Inspire Pharmaceuticals, Inc. pursuant to the terms of the Warrant Agreement,
and further acknowledges that _____ shares remain subject to purchase under the
terms of the Warrant Agreement.

                              INSPIRE PHARMACEUTICALS, INC.

                              By: _________________________________

                              Name: _______________________________

                              Title: ______________________________

                                       11
<PAGE>

                                  EXHIBIT III

                                TRANSFER NOTICE

     (To transfer or assign the foregoing Warrant Agreement execute this form
     and supply required information.  Do not use this form to purchase shares.)

     FOR VALUE RECEIVED, the foregoing Warrant Agreement and all rights
evidenced thereby are hereby transferred and assigned to:

               Print Name: ______________________________________

               Address: _________________________________________

               __________________________________________________

                         Dated: ___________________________________________

                         Holder's Signature: ______________________________

                         Holder's Address: ________________________________

                         __________________________________________________

                         Signature Guaranteed: ____________________________

NOTE: The signature to this transfer notice must correspond with the name as it
      appears on the face of the Warrant Agreement, without alteration or
      enlargement or any change whatever. Officers of corporations and those
      acting in a fiduciary or other representative capacity should file proper
      evidence of authority to assign the foregoing Warrant Agreement.

                                       12<PAGE>

                                                                   EXHIBIT 10.23

                             AMENDED AND RESTATED
                          INVESTORS' RIGHTS AGREEMENT

                         INSPIRE PHARMACEUTICALS, INC.

                               December 17, 1999
<PAGE>

                               TABLE OF CONTENTS

<TABLE>
<CAPTION>
                                                                                                          Page
<S>                                                                                                       <C>
1.   Participation Rights...............................................................................     2
     1.1      Definitions...............................................................................     2
     1.2      Participation Right.......................................................................     2
     1.3      Exercise of Right.........................................................................     3
     1.4      Overallotment.............................................................................     3
     1.5      Closing...................................................................................     3
     1.6      Failure to Exercise Right.................................................................     4

2.   Registration Rights................................................................................     4
     2.1      Definitions...............................................................................     4
     2.2      Demand Registration.......................................................................     5
     2.3      "Piggy-Back" Registration.................................................................     7
     2.4      Form S-3 Registration.....................................................................     9
     2.5      Obligations of the Company................................................................    10
     2.6      Furnish Information.......................................................................    11
     2.7      Expenses of Demand and S-3 Registrations..................................................    11
     2.8      Expenses of "Piggy-Back" Registration.....................................................    12
     2.9      Delay of Registration.....................................................................    12
     2.10     Indemnification...........................................................................    12
     2.11     Reports Under Securities Exchange Act of 1934.............................................    14
     2.12     "Market Stand-Off" Agreement..............................................................    15
     2.13     Termination of Registration Rights........................................................    16

3.   Transfers of Certain Rights........................................................................    16
     3.1      Transfer Restriction......................................................................    16
     3.2      Re-transfers..............................................................................    16
     3.3      Legend....................................................................................    16

4.   General............................................................................................    16
     4.1      Notices...................................................................................    16
     4.2      Termination of this Agreement.............................................................    17
     4.3      Entire Agreement..........................................................................    17
     4.4      Amendments and Waivers....................................................................    17
     4.5      Counterparts..............................................................................    18
     4.6      Captions..................................................................................    18
     4.7      Severability..............................................................................    18
     4.8      Governing Law.............................................................................    18
</TABLE>

<PAGE>

                             AMENDED AND RESTATED
                             --------------------
                          INVESTORS' RIGHTS AGREEMENT
                          ---------------------------

     THIS AMENDED AND RESTATED INVESTORS' RIGHTS AGREEMENT made as of December
17, 1999, is entered into by and among Inspire Pharmaceuticals, Inc. (the
"Company"), a Delaware corporation, and those investors identified on Schedule 1
                                                                      ----------
attached hereto (and any subsequent amendment thereto) (individually, an
"Investor" and collectively, the "Investors").

                            PRELIMINARY STATEMENTS
                            ----------------------

     A.   The Company and the Investors who acquired Series A Preferred Stock,
$0.001 par value, of the Company (the "Series A Stock"), and/or warrants
therefor (the "Series A Warrants"), and are identified as "Series A Investors"
on Schedule 1 attached hereto (the "Series A Investors"), and the Investors who
   ----------
acquired Series B Preferred Stock, $0.001 par value, of the Company (the "Series
B Stock"), and/or warrants therefor (the "Series B Warrants"), and are
identified as "Series B Investors" on Schedule 1 attached hereto (the "Series B
                                      ----------
Investors"), and the Investors who acquired Series E Preferred Stock, $0.001 par
value, of the Company (the "Series E Stock") and are identified as "Series E
Investors" on Schedule 1 attached hereto (the "Series E Investors") are parties
              ----------
to that certain Amended and Restated Investors' Rights Agreement dated as of
October 29, 1999 (the "Existing Investors' Rights Agreement").

     B.   The Company and the Investor identified as the "Series G Investor" on
Schedule 1 attached hereto (the "Series G Investor") are parties to that certain
----------
Series G Stock and Warrant Purchase Agreement dated December __, 1999 (the
"Series G Agreement") pursuant to which such Investor has purchased shares of
Series G Preferred Stock, $0.001 par value, of the Company (the "Series G
Stock") and warrants (the "Common Stock Warrants") exercisable for the
acquisition of shares of Common Stock.

     C.   In order to induce the Series G Investor to enter into and consummate
the transactions contemplated under the Series G Agreement, the Company and the
Series A Investors, Series B Investors and Series E Investors have agreed to
amend certain rights granted to such Investors pursuant to the Existing
Investors' Rights Agreement, and have agreed to amend and restate the Existing
Investors Rights Agreement to include the granting of certain rights to the
Series G Investor.

     NOW THEREFORE, in consideration of the mutual promises, covenants and
conditions hereinafter set forth and other good and valuable consideration, the
parties hereto hereby agree as follows:

                                      -1-
<PAGE>

1.   Participation Rights.
     --------------------

     1.1  Definitions.
          -----------

          (a)  "New Securities" shall mean (i) any capital stock of the Company
                --------------
whether or not currently authorized, (ii) all rights, options, or warrants to
purchase capital stock, and (iii) all securities of any type whatsoever that
are, or may become, convertible into capital stock; provided, however, that the
                                                    --------  -------
term "New Securities" shall not include (a) the Series A Stock or shares of
preferred stock, par value $0.001 per share, of the Company ("Preferred Stock")
or Common Stock, par value $0.001 per share of the Company ("Common Stock")
directly or indirectly issuable upon the conversion of the Series A Stock; (b)
the Series B Stock or shares of Common Stock or shares of Preferred Stock or
Common Stock directly or indirectly issuable upon conversion of the Series B
Stock; (c) the Series E Stock or shares of Common Stock directly or indirectly
issuable upon conversion of the Series E Stock; (d) shares of Common Stock
designated by vote of the Board of Directors of the Company, or options to
purchase such shares, that are issued or granted to employees or consultants of
the Company; (e) securities offered to the public pursuant to a registration
statement filed with the Securities and Exchange Commission; (f) securities
issued as a result of any stock split, stock dividend, or reclassification of
Common Stock, distributable on a pro rata basis to all holders of Common Stock;
(g) securities reissued to employees or consultants of the Company following the
Company's acquisition of such securities pursuant to restricted stock
arrangements with individuals who have terminated their relationship with the
Company or shares subject to options which are not exercised; and (h) securities
issued in connection with strategic alliances, joint ventures or partnerships,
or in connection with the licensing or acquisition by the Corporation of
technology or intellectual property, each as approved by the Board of Directors
of the Company.

          (b)  "Participation Rights Holder" shall include, for the purposes of
                ---------------------------
this Section 1, the Series A Investors, Series B Investors and Series E
Investors, as well as the general partners, officers, or other affiliates of
such Series A Investor, Series B Investor and Series E Investor, and a
Participation Rights Holder may apportion its pro rata share among itself and
such general partners, officers, and other affiliates in such proportions as it
deems appropriate.

     1.2  Participation Right. Each Participation Rights Holder shall be
          -------------------
entitled to a right to purchase, on a pro rata basis, all or any part of New
Securities which the Company may, from time to time, propose to sell and issue,
subject to the terms and conditions set forth below. Such Participation Rights
Holder's pro rata share shall equal a fraction of the New Securities being
issued, the numerator of which is the number of shares of Common Stock issued or
issuable upon conversion of the Series A Stock, Series B Stock, Series E Stock
or other Preferred Stock issued on conversion of Series A Stock, Series B Stock
or Series E Stock then held by a holder of Series A Stock, Series B Stock,
Series E Stock or other Preferred Stock issued on conversion of Series A Stock,
Series B Stock or Series E Stock, and the denominator of which is the total
number of shares of Common Stock then outstanding plus the number of shares of
Common Stock issuable

                                      -2-
<PAGE>

upon conversion of then outstanding Series A Stock, Series B Stock, Series E
Stock, Preferred Stock, or other convertible securities or on exercise of then
outstanding options, rights or warrants.

     1.3  Exercise of Right. In the event the Company intends to issue New
          -----------------
Securities, it shall give each Participation Rights Holder written notice of
such intention, describing the type of New Securities to be issued, the price
thereof, and the general terms upon which the Company proposes to effect such
issuance (the "Sale Notice"). Each Participation Rights Holder shall have twenty
(20) days from the date of any Sale Notice to agree to purchase all or part of
its pro rata share of such New Securities for the price and upon the general
terms and conditions specified in the Sale Notice by giving written notice to
the Company stating the quantity of New Securities to be so purchased ("Exercise
Notice"), provided, however, that in the event that the transaction described in
          --------  -------
a Sale Notice involves in whole or in part the payment of non-cash
consideration, or the payment of consideration over time, the Participation
Rights Holders shall have the right to elect, upon exercise of their rights set
forth in this Section 1, to pay to the Company in full consideration for the New
Securities the market price of such securities which shall be the present cash
value of the consideration described in the Sale Notice as determined by the
Board of Directors of the Company in good faith.

     1.4  Overallotment. In the event any Participation Rights Holder fails to
          -------------
exercise its right to purchase its pro rata share of New Securities, each
Participation Rights Holder who delivered an Exercise Notice for such
Participation Rights Holder's total pro rata share of New Securities (an
"Overallotment Participation Rights Holder") shall have a right to purchase such
Overallotment Participation Rights Holder's pro rata share of the New Securities
with respect to which Participation Rights Holders have failed to exercise their
rights hereunder ("Remaining New Securities"). In such case, within twenty five
(25) days after the delivery of the Sale Notice, the Company shall provide
written notice ("Overallotment Notice") to each Overallotment Participation
Rights Holder, which shall state the total amount of Remaining New Securities,
and the pro rata portion of such Remaining New Securities which each
Overallotment Participation Rights Holder is entitled to purchase. Each
Overallotment Participation Rights Holder wishing to purchase such Remaining
Securities shall amend such Overallotment Participation Rights Holder's Exercise
Notice in writing within five (5) days from the date of delivery of the
Overallotment Notice. For the purpose of this Section 1.4, an Overallotment
Participation Rights Holder's pro rata share of the Remaining New Securities
shall be calculated as provided in Section 1.2, except that the denominator of
the fraction shall be the total number of shares of Common Stock issued or
issuable upon conversion of Series A Stock, Series B Stock or Series E Stock
held by all of the Overallotment Participation Rights Holders but shall exclude
shares of Common Stock issuable on conversion of other Preferred Stock or other
convertible securities or on exercise of options, rights or warrants.

     1.5  Closing. The closing of the purchase of New Securities by the
          -------
Participation Rights Holders exercising their rights hereunder ("Participating
Participation Rights Holders") shall take place at such location, date and time
as the

                                      -3-
<PAGE>

parties shall agree but not later than the later of (i) forty (40) days
following the delivery of the Sale Notice, or (ii) ten (10) days following the
delivery of the Overallotment Notice. At the closing, the Company shall deliver
to the Participating Participation Rights Holders (i) certificates representing
all of the New Securities to be purchased, and (ii) such other agreements
executed by the Company which grant any rights or privileges to the
Participating Participation Rights Holders as are being granted to the other
purchasers in such issuance, and in any event, at the request of the
Participating Participation Rights Holders, a duly executed certificate
reasonably satisfactory to the Participating Participation Rights Holders
containing a representation and warranty that, upon issuance or transfer of such
securities to the Participating Participation Rights Holders that the
Participating Participation Rights Holders will be the legal and beneficial
owners of such securities with good title thereto, free and clear of all
mortgages, liens, charges, security interests, adverse claims, pledges,
encumbrances and demands whatsoever, and that the Company has the absolute right
to issue or transfer such securities to the Participating Participation Rights
Holders without the consent or approval of any other person. At the closing, the
Participating Participation Rights Holders shall deliver to the Company (i)
payment for the New Securities, and (ii) such other agreements executed by the
other purchasers in such issuance which include representations by such
purchasers to the Company or restrict such purchaser's rights with respect to
the New Securities, and in any event, at the request of the Company, a duly
executed certificate reasonably satisfactory to the Company containing such
representations and warranties of the Participating Participation Rights Holders
with respect to federal and state securities laws. The certificates representing
the equity securities may contain a legend stating that they are issued subject
to the registration requirements of the Act, as amended, and applicable state
securities laws.

     1.6  Failure to Exercise Right. In the event the Participation Rights
          -------------------------
Holders fail to exercise the foregoing participation right with respect to any
New Securities within the periods specified by Sections 1.3 and 1.4 above, the
Company may within one hundred and twenty (120) days after the delivery of the
Sale Notice sell any or all of such New Securities not agreed to be purchased by
the Participation Rights Holders, at a price and upon general terms no more
favorable to the Participation Rights Holders thereof than specified in the Sale
Notice. In the event the Company has not sold such New Securities within such
120-day period, the Company shall not thereafter issue or sell any New
Securities without first offering such New Securities to the Participation
Rights Holders in the manner provided in Section 1.3

     2.   Registration Rights. The Company covenants and agrees as follows:
          -------------------

          2.1  Definitions.  As used in this Section 2, the following terms
               -----------
shall have the following meanings:

               (a)  "Act" means the Securities Act of 1933, as amended.
                     ---

               (b)  "Form S-1" means such form under the Act as in effect on the
date hereof, or any registration form under the Act subsequently adopted by the
SEC which

                                      -4-
<PAGE>

permits the registration of securities under the Act for which no other form is
authorized or prescribed.

               (c)  "Form S-3" means such form under the Act as in effect on
                     --------
the date hereof or any registration form under the Act subsequently adopted by
the SEC which permits inclusion or incorporation of substantial information by
reference to other documents filed by the Company with the SEC, including but
not limited to Form A and Form B, as proposed to be adopted by the SEC and as
described in Securities Act Release No. 33-7606.

               (d)  "Holder" means (i) an Investor and any persons or entities
                     ------
to whom the rights granted under this Section 2 are transferred by the Investor
and (ii) their successors or assigns as permitted under Section 3 below.

               (e)  "Investor"  shall include those investors  listed on the
                     --------
Schedule of Investors, annexed hereto as Schedule 1.
---------------------

               (f)  "1934 Act" shall mean the Securities Exchange Act of 1934,
                     --------
as amended.

               (g)  The terms "register," "registered," and "registration"
                               --------    ----------        ------------
refer to a registration effected by preparing and filing a registration
statement or similar document in compliance with the Act, and the declaration or
ordering of effectiveness of such registration statement or document.

               (h)  "Registrable Securities" means (i) the Common Stock issuable
                     ----------------------
or issued upon conversion of the Series A Stock, Series B Stock, Series E Stock,
Series G Stock or other Preferred Stock issued upon conversion of the Series A
Stock, Series B Stock, Series E Stock or Series G Stock, including the Common
Stock issuable or issued upon conversion of the Series A Stock and Series B
Stock issued upon exercise of the Series A Warrants and the Series B Warrants,
(ii) any Common Stock issued upon exercise of the Common Stock Warrants which
shall be deemed to be included as Registrable Securities issued upon conversion
of the Series G Stock for purposes of calculating the holders of Registrable
Securities issued from the Series G Stock, (iii) any Common Stock issued
pursuant to the Series G Agreement and (iv) any Common Stock of the Company
issued as (or issuable upon the conversion or exercise of any warrant, right, or
other security which is issued as) a dividend or other distribution with respect
to, or in exchange for or in replacement of, the shares referenced in (i), (ii)
or (iii) above, excluding in all cases, however, any Registrable Securities sold
by a person in a transaction in which the rights under this Section 2 are not
properly assigned.

               (i)  "Outstanding Registrable Securities" shall mean the number
                     ----------------------------------
of shares of Common Stock outstanding that are, and the number of shares of
Common Stock issuable pursuant to then exercisable or convertible securities
which are, Registrable Securities.

                                      -5-
<PAGE>

               (j)  "SEC" shall mean the Securities and Exchange Commission.
                     ---

          2.2  Demand Registration.
               -------------------

               (a)  If the Company shall receive (i) at any time after March 10,
2000, a written notice from the Holders of at least fifty percent (50%) of the
Outstanding Registrable Securities issued or issuable upon the conversion of the
Series A Stock or other Preferred Stock issued upon conversion of the Series A
Stock, or issued as a dividend or distribution with respect thereto, or (ii) at
any time after April 8, 2002, a written notice from the holders of at least
fifty percent (50%) of the Outstanding Registrable Securities issued or issuable
upon the conversion of the Series A Stock or Series B Stock or other Preferred
Stock issued upon conversion of the Series A Stock or Series B Stock, or issued
as a dividend or distribution with respect thereto, or (iii) at any time after
December 31, 2002, a written notice from the Holders of at least fifty percent
(50%) of the Outstanding Registrable Securities issued upon conversion of any
two of the following series of Preferred Stock: the Series A Stock, Series B
Stock, Series E Stock, Series G Stock or other Preferred Stock issued or
issuable upon conversion of the Series A Stock, Series B Stock, Series E Stock
or Series G Stock, or issued as a dividend or distribution with respect thereto,
requesting that the Company effect a registration statement under the Act
covering the registration of all or part of the Registrable Securities having an
aggregate offering price to the public of not less than $5,000,000, then the
Company shall:

                    (i)  within ten (10) days of the receipt thereof, give
written notice of such request to all Holders; and

                    (ii) effect as soon as practicable, and in any event within
ninety (90) days of the receipt of such request, the registration under the Act
of all Registrable Securities which the Holders request to be registered,
subject to the limitations of Section 2.2(b), by notice to the Company within
thirty (30) days of the mailing of such notice by the Company in accordance with
Section 2.2(a)(i).

               (b)  If the Holders initiating the registration request hereunder
("Initiating Holders") intend to distribute the Registrable Securities covered
by their request by means of an underwriting, they shall so advise the Company
as a part of their request pursuant to Section 2.2(a) and the Company shall
include such information in the written notice referred to in Section 2.2(a).
The underwriter will be selected by the Company and shall be reasonably
acceptable to a majority in interest of the Initiating Holders. In such event,
the right of any Holder to include Registrable Securities in such registration
shall be conditioned upon such Holder's participating in such underwriting and
the inclusion of such Holder's Registrable Securities in the underwriting
(unless otherwise mutually agreed by a majority in interest of the Initiating
Holders and such Holder) to the extent provided herein. All Holders proposing to
distribute their securities through such underwriting shall (together with the
Company as provided in Section 2.5(e)) enter into an underwriting agreement in
customary form with the underwriter or underwriters selected for such
underwriting. Notwithstanding any other provision of this

                                      -6-
<PAGE>

Section 2.2, if the underwriter advises the Initiating Holders in writing that
marketing factors require a limitation of the number of shares to be
underwritten, then the Initiating Holders shall so advise all Holders of
Registrable Securities which would otherwise be underwritten pursuant hereto,
and the number of shares of Registrable Securities that may be included in the
underwriting shall be allocated first amongst all Holders thereof, including the
Initiating Holders, in proportion (as nearly as practicable) to the amount of
Registrable Securities of the Company owned by each Holder; provided, however,
                                                            --------  -------
that the number of shares of Registrable Securities to be included in such
underwriting shall not be reduced unless all other securities are first entirely
excluded from the underwriting.

               (c)  Notwithstanding the foregoing, if the Company shall furnish
to Holders requesting registration pursuant to this Section 2.2, a certificate
signed by the Chief Executive Officer of the Company stating that in the good
faith judgment of the Board of Directors of the Company, it would be seriously
detrimental to the Company and its stockholders for a registration statement to
be filed and it is therefore essential to defer the filing of such registration
statement, the Company shall have the right to defer taking action with respect
to such filing for a period of not more than one hundred twenty (120) days after
receipt of the request of the Initiating Holders.

               (d)  In addition, the Company shall not be obligated to effect,
or to take any action to effect, any registration pursuant to this Section 2.2
after the Company has effected two (2) registrations on Form S-1 or its then
equivalent pursuant to this Section 2.2 and such registration statement has been
declared or ordered effective and the sales of Registrable Securities under such
registration statement have closed.

               (e)  The company shall not be obligated to effect, or to take any
action to effect, any registration pursuant to this Section 2.2 during the one
hundred eighty (180) day period commencing with the date of the Company's
initial public offering.

               (f)  No incidental right under this Section 2.2 shall be
construed to limit any registration required under Section 2.3 or Section 2.4
herein.

          2.3  "Piggy-Back" Registration.
                ------------------------

               (a)  If (but without any obligation to do so) the Company
proposes to register (including for this purpose a registration effected by the
Company for stockholders other than the Holders) any of its stock or other
securities under the Act in connection with the public offering of such
securities solely for cash (other than a registration relating solely to the
sale of securities to participants in a stock plan, a registration on any form
which does not include substantially the same information as would be required
to be included in a registration statement covering the sale of the Registrable
Securities, or a registration on Form S-4 (or any successor form) relating
solely to a transaction pursuant to the SEC's Rule 145), the Company shall, at
such time, promptly give each Holder written notice of such registration. Upon
the written request of each Holder given within twenty (20) days after mailing
of such notice by the

                                      -7-
<PAGE>

Company in accordance with Section 4.2, the Company shall, subject to the
provisions of Section 2.3(b), cause to be registered under the Act all of the
Registrable Securities that each such Holder has requested to be registered.

               (b)  In connection with any offering involving an underwriting of
shares of the Company's capital stock, the Company shall not be required under
this Section 2.3 to include any of the Holders' securities in such underwriting
unless they accept the terms of the underwriting as agreed upon between the
Company and the underwriters selected by it (or by other persons entitled to
select the underwriters), and then only in such quantity as the underwriters
determine in their sole discretion will not jeopardize the success of the
offering by the Company. If the total amount of securities, including
Registrable Securities, requested by stockholders to be included in such
offering exceeds the amount of securities to be sold (other than by the Company)
that the underwriters determine in their sole discretion is compatible with the
success of the offering, then the Company shall be required to include in the
offering only that number of such securities, including Registrable Securities,
which the underwriters determine in their sole discretion will not jeopardize
the success of the offering; provided, however, there shall first be excluded
                             --------  -------
from such registration statement all shares of Common Stock sought to be
included therein by (i) any director, consultant, officer, or employee of the
Company or any subsidiary, and (ii) stockholders exercising any contractual or
incidental registration rights subordinate and junior to the rights of the
Holders of Registrable Securities. If after such shares are excluded, the
underwriters shall determine in their sole discretion that the number of
securities which remain to be included in the offering exceeds the amount of
securities to be sold that the underwriters determine is compatible with the
success of the offering, then the Registrable Securities to be included, if any,
shall be apportioned pro rata among the Holders providing notice of their desire
to participate in the offering according to the total amount of securities
entitled to be included therein owned by each selling Holder or in such other
proportions as shall mutually be agreed to by such Holders; provided, however,
                                                            --------  -------
there shall first be excluded from such registration statement all shares of
Common Stock sought to be included therein which are issued or issuable upon
conversion of the Series D Stock; provided, further there shall next be excluded
                                  --------  -------
from such registration all shares of Common Stock sought to be included therein
which are issued or issuable upon conversion of the Series C Stock; and
provided, further, only after all shares of Common Stock issued or issuable upon
--------  -------
conversion of the Series C Stock and Series D Stock have been excluded from such
registration shall any shares of Common Stock sought to be included therein
which are issued or issuable upon conversion of the Series A Stock, Series B
Stock, Series E Stock or Series G Stock be excluded. For purposes of the
preceding sentence concerning apportionment, for any selling Holder which is a
partnership, limited liability company or corporation, the partners, retired
partners, members, former members, stockholders, parent or subsidiary of such
Holder, or the estates and family members of any such partners, retired
partners, members, former members and any trusts for the benefit of any of the
foregoing persons shall be deemed to be a single "selling Holder," and any pro-
rata reduction with respect to such "selling Holder" shall be based upon the
aggregate amount of shares carrying registration rights owned by all entities
and individuals included in such "selling Holder," as defined in this sentence.

                                      -8-
<PAGE>

               (c)  No incidental right under this Section 2.3 shall be
construed to limit any registration required under Section 2.2 or Section 2.4
herein.

          2.4  Form S-3 Registration. In case the Company shall receive from any
               ---------------------
Holder or Holders of (i) at least fifty percent (50%) of the Common Stock issued
or issuable upon conversion of the Series A Stock; (ii) at least fifty percent
(50%) of the Common Stock issued or issuable upon conversion of the Series B
Stock; (iii) at least fifty percent (50%) of the Common Stock issued or issuable
upon conversion of the Series E Stock; or (iv) at least fifty percent (50%) of
the Common Stock issued or issuable upon conversion of the Series G Stock, a
written request or requests that the Company effect a registration on Form S-3
and any related qualification or compliance with respect to all or a part of the
Registrable Securities owned by such Holder or Holders, the Company agrees:

               (a)  to promptly give written notice of the proposed registration
and any related qualification or compliance, to all other Holders;

               (b)  as soon as practicable after receiving such a request, to
effect such registration and all such qualifications and compliances as may be
so requested and as would permit or facilitate the sale and distribution of all
or such portion of such Holder's or Holders' Registrable Securities as are
specified in such request, together with all or such portion of the Registrable
Securities of any other Holder or Holders joining in such request as are
specified in a written request given within fifteen (15) days after receipt of
such written notice from the Company; provided, however, that the Company shall
                                      --------  -------
not be obligated to effect any such registration, qualification, or compliance
pursuant to this Section 2.4: (i) if Form S-3 is not available for such offering
by the Holders; (ii) if the Holders, together with the holders of any other
securities of the Company entitled to inclusion in such registration, propose to
sell Registrable Securities and such other securities (if any) at an aggregate
price to the public of less than $500,000; (iii) if the Company shall furnish to
the Holders making a request a certificate signed by the Chief Executive Officer
of the Company stating that in the good faith judgment of the Board of Directors
of the Company, it would be seriously detrimental to the Company and its
stockholders for such Form S-3 registration to be effected at such time, in
which event the Company shall have the right to defer the filing of the Form S-3
registration statement for a period of not more than ninety (90) days after
receipt of the request of the Holder or Holders under this Section 2.4;
provided, however, that the Company shall not utilize this right with respect to
--------  -------
any one request more than once in any six (6) month period and provided further
                                                               -------- -------
that no Holder or Holders shall be entitled to make a request for registration
pursuant to this Section 2.4 during any such period of deferment; or (iv) until
the next calendar year if the Company has effected two (2) registrations on Form
S-3 (or its then equivalent) pursuant to this Section 2.4 in a calendar year and
such registrations have been declared or ordered effective and the sales of
Registrable Securities under such registration statement have closed.

                                      -9-
<PAGE>

               (c)  Registrations effected pursuant to this Section 2.4 shall
not be counted as demands for registration or registrations effected pursuant to
Sections 2.2 or 2.3, respectively.

          2.5  Obligations of the Company. Whenever required under this Section
               --------------------------
2 to effect the registration of any Registrable Securities, the Company shall,
as expeditiously as reasonably possible (but subject to providing counsel to the
Holders with a reasonable opportunity to review and comment on all documents):

               (a)  Prepare and file with the SEC a registration statement
with respect to such Registrable Securities and use its best efforts to cause
such registration statement to become effective, and, upon the request of the
Holders of a majority of the Registrable Securities registered thereunder, keep
such registration statement effective for a period of up to one hundred twenty
(120) days or, if earlier, until the distribution contemplated in the
Registration Statement has been completed; provided, however, that (i) such
                                           --------  -------
120-day period shall be extended for a period of time equal to the period the
Holder refrains from selling any securities included in such registration at the
request of an underwriter of Common Stock (or other securities) of the Company,
and (ii) in the case of any registration of Registrable Securities on Form S-3
which are intended to be offered on a continuous or delayed basis, such 120-day
period shall be extended, if necessary, to keep the registration statement
effective until all such Registrable Securities are sold, provided that Rule
415, or any successor rule under the Act, permits an offering on a continuous or
delayed basis, and provided further that applicable rules under the Act
governing the obligation to file a post-effective amendment permit, in lieu of
filing a post-effective amendment which (i) includes any prospectus required by
Section 10(a)(3) of the Act, or (ii) reflects facts or events representing a
material or fundamental change in the information set forth in the registration
statement, the incorporation by reference of information required to be included
in (i) and (ii) above to be contained in periodic reports filed pursuant to
Section 13 or 15(d) of the 1934 Act in the registration statement.

               (b)  Prepare and file with the SEC such amendments and
supplements to such registration statement and the prospectus used in connection
with such registration statement as may be necessary to comply with the
provisions of the Act with respect to the disposition of all securities covered
by such registration statement in accordance with each Holder's intended method
of disposition.

               (c)  Furnish to the Holders such numbers of copies of a
prospectus, including a preliminary prospectus, in conformity with the
requirements of the Act, and such other documents as they may reasonably request
in order to facilitate the disposition of Registrable Securities owned by the
Holders.

               (d)  Use its best efforts to register and qualify the securities
covered by such registration statement under such other securities or Blue Sky
laws of such jurisdictions as shall be reasonably requested by the Holders and
any managing underwriter; provided that the Company shall not be required in
connection therewith or as a condition thereto to qualify to do business or to
file a general consent to service of

                                      -10-
<PAGE>

process in any such states or jurisdictions, unless the Company is already
subject to service in such jurisdiction and except as may be required by the
Act.

               (e)  In the event of any underwritten public offering, enter
into and perform its obligations under an underwriting agreement, in usual and
customary form, with the managing underwriter of such offering. Each Holder
participating in such underwriting shall also enter into and perform its
obligations under such an agreement.

               (f)  Promptly notify each Holder of Registrable Securities
covered by such registration statement at any time when a prospectus relating
thereto is required to be delivered under the Act as a result of the happening
of any event as a result of which the prospectus included in such registration
statement, as then in effect, includes an untrue statement of a material fact or
omits to state a material fact required to be stated therein or necessary to
make the statements therein not misleading in the light of the circumstances
then existing.

               (g)  Cause all such Registrable Securities registered pursuant
hereunder to be listed on each securities exchange on which similar securities
issued by the Company are then listed.

               (h)  Provide a transfer agent and registrar for all Registrable
Securities registered pursuant hereunder and a CUSIP number for all such
Registrable Securities, in each case not later than the effective date of such
registration.

               (i)  Furnish, at the request of any Holder requesting
registration of Registrable Securities pursuant to this Section 2, on the date
that such Registrable Securities are delivered to the underwriters for sale in
connection with a registration pursuant to this Section 2, if such Securities
are being sold through underwriters, copies of (i) the opinion, dated as of such
date, of the counsel representing the Company for the purposes of such
registration given to the underwriters in such underwritten public offering,
which opinion shall be in such form as is reasonably satisfactory to counsel to
the underwriters, and (ii) the letter dated as of such date, from the
independent certified public accountants of the Company, to the underwriters in
such underwritten public offering, addressed to the underwriters, which letter
shall be in such form as is reasonably satisfactory to counsel to the
underwriters.

          2.6  Furnish Information. It shall be a condition precedent to the
               -------------------
obligations of the Company to take any action pursuant to this Section 2 with
respect to the Registrable Securities of any selling Holder that such Holder
shall furnish to the Company such information regarding itself, the Registrable
Securities held by it, and the intended method of disposition of such securities
as shall be required to effect the registration of such Holder's Registrable
Securities.

          2.7  Expenses of Demand and S-3 Registrations. The Company shall pay
all expenses other than underwriting discounts and commissions incurred in
connection with registrations, filings, or qualifications pursuant to Sections
2.2 and 2.4, including without

                                      -11-
<PAGE>

limitation (i) all registration, filing, and qualification fees (including, but
not limited to, filing fees with the SEC, fees due to the National Association
of Securities Dealers and fees due for listing on any stock exchange or for
qualifying for quotation on the Nasdaq system; (ii) printers and accounting
fees; (iii) fees and disbursements of counsel selected by the Company; and (iv)
the reasonable fees and disbursements of one counsel for the selling Holders;
provided, however, that the Company shall not be required to pay for any
--------  -------
expenses of any registration proceeding begun pursuant to Section 2.2 or 2.4 if
the registration request is subsequently withdrawn at the request of the Holders
of a majority of the Registrable Securities to be registered (in which case all
Holders participating in the registration shall bear such expenses), unless the
Holders of a majority of the Registrable Securities agree to forfeit their
rights to one registration during the applicable period under, as the case may
be, Section 2.2 (demand registration) or Section 2.4 (S-3 registration);
provided further, however, that if at the time of such withdrawal, the Holders
-------- -------  -------
have either (i) learned of a material adverse change in the conditions,
business, or prospects of the Company from that known to the Holders at the time
of their request or (ii) been informed by the underwriters of such registration
that more than 20% of the Registrable Securities requested for registration
shall not be includable therein due to market factors, and in either such case
the Holders have withdrawn the request with reasonable promptness following such
disclosure, then the Holders shall not be required to pay such expenses and
shall retain their rights pursuant to Sections 2.2 and 2.4.

     2.8  Expenses of "Piggy-Back" Registration. The Company shall pay all
          -------------------------------------
expenses incurred in connection with any registration, filing, or qualification
of Registrable Securities with respect to the registrations pursuant to Section
2.3 for each Holder, including without limitation all registration, filing, and
qualification fees, printers and accounting fees relating or apportionable
thereto, and the fees and disbursements of one counsel for the selling Holders
selected by them, but excluding underwriting discounts and commissions relating
to the Registrable Securities.

     2.9  Delay of Registration. No Holder shall have any right to obtain or
          ---------------------
seek an injunction restraining or otherwise delaying any such registration as
the result of any controversy that might arise with respect to the
interpretation or implementation of this Section 2.

     2.10 Indemnification.  In the event any Registrable Securities are included
          ---------------
in a registration statement under this Section 2:

          (a)  To the extent permitted by law, the Company will indemnify and
hold harmless each Holder, any underwriter (as defined in the Act) for such
Holder, and each person (if any) who controls such Holder or underwriter within
the meaning of the Act or the 1934 Act, against any losses, claims, damages, or
liabilities (joint or several) to which they may become subject under the Act,
the 1934 Act, or other federal or state law, insofar as such losses, claims,
damages, or liabilities (or actions in respect thereof) arise out of or are
based upon any of the following statements, omissions, or violations
(collectively a "Violation"): (i) any untrue statement or alleged untrue
statement of a material fact contained in such registration statement of a
material fact contained in such

                                      -12-
<PAGE>

registration statement, including any preliminary prospectus or final prospectus
contained therein or any amendments or supplements thereto, (ii) the omission or
alleged omission to state therein a material fact required to be stated therein,
or necessary to make the statements therein not misleading, or (iii) any
violation or alleged violation by the Company of the Act, the 1934 Act, any
state securities law, or any rule or regulation promulgated under the Act, the
1934 Act, or any state securities law; and the Company will pay to each such
Holder, underwriter, or controlling person, as incurred, any legal or other
expenses reasonably incurred by them in connection with investigating or
defending any such loss, claim, damage, liability, or action; provided, however,
that the indemnity agreement contained in this Section 2.10(a) shall not apply
to amounts paid in settlement of any such loss, claim, damage, liability, or
action if such settlement is effected without the consent of the Company (which
consent shall not be unreasonably withheld), nor shall the Company be liable in
any such case for any such loss, claim, damage, liability, or action to the
extent that it arises out of or is based upon a Violation which occurs in
reliance upon and in conformity with written information furnished expressly for
use in connection with such registration by any such Holder, underwriter, or
controlling person.

          (b)  To the extent permitted by law, each selling Holder severally and
not jointly will indemnify and hold harmless the Company, each of its directors,
each of its officers who has signed the registration statement, each person (if
any) who controls the Company within the meaning of the Act, any underwriter,
any other Holder selling securities in such registration statement, and any
controlling person of any such underwriter or other Holder, against any losses,
claims, damages, or liabilities (joint or several) to which any of the foregoing
persons may become subject, under the Act, the 1934 Act or other federal or
state law, insofar as such losses, claims, damages, or liabilities (or actions
in respect thereto) arise out of or are based upon any Violation, in each case
to the extent (and only to the extent) that such Violation occurs in reliance
upon and in conformity with written information furnished by such Holder
expressly for use in connection with such registration; and each such Holder
will pay, as incurred, any legal or other expenses reasonably incurred by any
person intended to be indemnified pursuant to this Section 2.10(b), in
connection with investigating or defending any such loss, claim, damage,
liability, or action; provided, however, that the indemnity agreement contained
                      --------  -------
in this Section 2.10(b) shall not apply to amounts paid in settlement of any
such loss, claim, damage, liability, or action if such settlement is effected
without the consent of the Holder, which consent shall not be unreasonably
withheld; and further provided that in no event shall any indemnity under this
Section 2.10(b) exceed the gross proceeds from the offering received by such
Holder.

          (c)  Promptly after receipt by an indemnified party under this
Section 2.10 of notice of the commencement of any action (including any
governmental action), such indemnified party will, if a claim in respect thereof
is to be made against any indemnifying party under this Section 2.10, deliver to
the indemnifying party a written notice of the commencement thereof and the
indemnifying party shall have the right to participate in, and, similarly
noticed, to assume the defense thereof with counsel mutually satisfactory to the
parties; provided, however, that an indemnified party (together with all
         --------  -------

                                      -13-
<PAGE>

other indemnified parties which may be represented without conflict by one
counsel) shall have the right to retain one separate counsel and participate in
the defense, with the fees and expenses to be paid by the indemnifying party, if
representation of such indemnified party by the counsel retained by the
indemnifying party would be inappropriate due to actual or potential differing
interests between such indemnified party and any other party represented by such
counsel in such proceeding. The failure to deliver written notice to the
indemnifying party within a reasonable time of the commencement of any such
action, if prejudicial to its ability to defend such action, shall relieve such
indemnifying party of any liability to the indemnified party under this Section
2.10, but the omission so to deliver written notice to the indemnifying party
will not relieve it of any liability that it may have to any indemnified party
otherwise than under this Section 2.10.

          (d)  If the indemnification provided for in this Section 2.10 is held
by a court of competent jurisdiction to be unavailable to an indemnified party
with respect to any loss, liability, claim, damage, or expense referred to
therein, then the indemnifying party, in lieu of indemnifying such indemnified
party hereunder, shall contribute to the amount paid or payable by such
indemnified party as a result of such loss, liability, claim, damage, or expense
in such proportion as is appropriate to reflect the relative fault of the
indemnifying party, on the one hand, and of the indemnified party, on the other,
in connection with the statements or omissions that resulted in such loss,
liability, claim, damage, or expense as well as any other relevant equitable
considerations. The relative fault of the indemnifying party and of the
indemnified party shall be determined by reference to, among other things,
whether the untrue or alleged untrue statement of a material fact or the
omission to state a material fact relates to information supplied by the
indemnifying party or by the indemnified party and the parties' relative intent,
knowledge, access to information, and opportunity to correct or prevent such
statement or omission.

          (e)  Notwithstanding the foregoing, to the extent that the provisions
on indemnification and contribution contained in the underwriting agreement
entered into in connection with the underwritten public offering are in conflict
with the foregoing provisions, the provisions in the underwriting agreement
shall control. Notwithstanding the foregoing, the failure of the underwriting
agreement to address an issue covered by this agreement shall not be deemed to
be a conflict.

          (f)  The obligations of the Company and Holders under this Section
2.10 shall survive the completion of any offering of Registrable Securities in a
registration statement under this Section 2, and otherwise.

     2.11 Reports Under Securities Exchange Act of 1934. With a view to making
          ---------------------------------------------
available to the Holders the benefits of Rule 144 promulgated under the Act and
any other rule or regulation of the SEC that may at any time permit a Holder to
sell securities of the Company to the public without registration or suppressant
to a registration on Form S-3, the Company agrees to use its best efforts:

                                      -14-
<PAGE>

          (a)  to make and keep public information available, as those terms are
understood and defined in SEC Rule 144, at all times after ninety (90) days
after the effective date of the first registration statement filed by the
Company for the offering of its securities to the general public;

          (b)  to take such action, including the voluntary registration of its
Common Stock under Section 12 of the 1934 Act, as is necessary to enable the
Holders to utilize Form S-3 for the sale of their Registrable Securities, such
action to be taken as soon as practicable after the end of the fiscal year in
which the first registration statement filed by the Company for the offering of
its securities to the general public is declared effective;

          (c)  to file with the SEC in a timely manner all reports and other
documents required of the Company under the Act and the 1934 Act; and

          (d)  to furnish to any Holder, so long as the Holder owns any
Registrable Securities, forthwith upon request (i) a written statement by the
Company that it has complied with the reporting requirements of SEC Rule 144 (at
any time after ninety (90) days after the effective date of the first
registration statement filed by the Company), the Act and the 1934 Act (at any
time after it has become subject to such reporting requirements), or that it
qualifies as a registrant whose securities may be resold pursuant to Form S-3
(at any time after it so qualifies), (ii) a copy of the most recent annual or
quarterly report of the Company and such other reports and documents so filed by
the Company, and (iii) such other information as may be reasonably requested in
availing any Holder of any rule or regulation of the SEC which permits the
selling of any such securities without registration or pursuant to such form.

          2.12 "Market Stand-Off" Agreement. Each Investor hereby agrees that,
               ----------------------------
during the period of duration (not to exceed one hundred eighty (180) days)
specified by the Company and an underwriter of Common Stock or other securities
of the Company, following the effective date of a registration statement of the
Company filed under the Act, such Investor shall not, to the extent requested by
the Company and such underwriter, directly or indirectly sell, offer to sell,
contract to sell (including, without limitation, any short sale), grant any
option to purchase, or otherwise transfer or dispose of (other than to donees
who agree to be similarly bound) any securities of the Company held by it at any
time during such period except Common Stock included in such registration;
provided, however, that all officers, directors and holders of 10% of the
--------  -------
outstanding shares of the Company enter into similar agreements.

               In order to enforce the foregoing covenant, the Company may
impose stop-transfer instructions with respect to the Registrable Securities of
an Investor (and the shares or securities of every other person subject to the
foregoing restriction) until the end of such period.

               Notwithstanding the foregoing, the obligations described in this
Section 2.12 shall not apply to a registration relating solely to employee
benefit plans on Form S-

                                      -15-
<PAGE>

1 or Form S-8 or similar forms which may be promulgated in the future, or a
registration relating solely to an SEC Rule 145 transaction on Form S-4 or
similar forms which may be promulgated in the future.

     2.13 Termination of Registration Rights. No Holder shall be entitled to
          ----------------------------------
exercise any right provided for in this Section 2 after five (5) years following
the consummation of the sale of securities pursuant to a registration statement
filed by the Company under the Act in connection with the initial firm
commitment underwritten offering of its securities to the general public.

3.   Transfers of Certain Rights.
     ---------------------------

     3.1  Transfer Restriction. The rights granted to the Investors may be
          --------------------
transferred or succeeded to only by (i) any other Investor or any general or
limited partner, officer, parent or subsidiary corporation or other affiliate of
any Investor, or (ii) any other person or entity that acquires at least five
percent (5%) of the Registrable Shares, or (iii) who acquires at least 25% of
the Series G Stock or 25% of the Registrable Shares issued or issuable upon the
conversion of the Series G Stock; provided, however, that the Company is given
written notice by the transferee at the time of such transfer stating the name
and address of the transferee and identifying the securities with respect to
which such rights are being assigned.

     3.2  Re-transfers. A transferee to whom rights are transferred pursuant to
          ------------
this Section 3 may not again transfer such rights to any other person or entity,
other than as provided in Section 3.1 above.

     3.3  Legend. Each certificate representing the shares of Series A Stock,
          ------
Series B Stock, Series E Stock and Series G Stock shall bear a legend indicating
that any holder of the Series A Stock, Series B Stock, Series E Stock and Series
G Stock shall be subject to this Agreement.

4.   General.
     -------

     4.1  Notices. All notices, requests, consents and other communications
          -------
under this Agreement shall be in writing and shall be delivered by hand, by
telecopier, by overnight mail or mailed by first class certified or registered
mail, return receipt requested, postage prepaid:

                 If to the Company:

                    Inspire Pharmaceuticals, Inc.
                    4222 Emperor Boulevard
                    Suite 470
                    Durham, N.C. 27703
                    Attention: President

                                      -16-
<PAGE>

(or at such other address as may have been furnished in writing to the Investors
by the Company)

                 with a copy to:

                    Diane M. Frenier, Esq.
                    Smith, Stratton, Wise, Heher & Brennan
                    600 College Road East
                    Princeton, NJ 08540-6636

If to an Investor or a Holder, as applicable, at its address set forth on
Schedule 1 to this Agreement (or at such other address as may have been
furnished in writing to the Company by such Investor).

Notices provided in accordance with this Section 4.1 shall be deemed delivered
upon personal delivery, receipt by telecopy or overnight mail, or 48 hours after
deposit in the mail in accordance with the above.

     4.2  Termination of this Agreement. Section 1 of this Agreement shall
          -----------------------------
terminate and shall be of no further force and effect upon the conversion of all
outstanding shares of Series A Stock, Series B Stock and Series E Stock (or any
shares of other preferred stock issued upon the conversion of Series A Stock,
Series B Stock or Series E Stock) into Common Stock pursuant to the Company's
Restated Certificate of Incorporation. This Agreement shall terminate in its
entirety upon the termination of registration rights pursuant to Section 2,
except that Sections 2.10 and 4.8 shall survive such termination.

     4.3  Entire Agreement. This Agreement embodies the entire agreement and
          ----------------
understanding between the parties hereto with respect to the subject matter
hereof and supersedes all prior agreements and understandings relating to such
subject matter, including without limitation, the Existing Investors' Rights
Agreement.

     4.4  Amendments and Waivers. Except as otherwise expressly set forth in
          ----------------------
this Agreement, any term of this Agreement may be amended and the observance of
any term of this Agreement may be waived (either generally or in a particular
instance and either retroactively or prospectively) as follows:

          (a)  With respect to Section 1, with the written consent of the
Company and fifty percent (50%) of the Participation Rights Holders, calculated
based on the number of shares of Preferred Stock included in each Participation
Rights Holder's participation rights pursuant to Section 1.

          (b)  With respect to Section 2, with the written consent of the
Company and the Holders of not less than fifty percent (50%) of the Registrable
Shares.

                                      -17-
<PAGE>

          (c)  With respect to Sections 3 and 4, with the written consent of the
Company and not less than fifty percent (50%) of the Holders, calculated based
on the number of shares of Registrable Securities held by each such Holders,
except that any amendment of any provision of this Section 4.4 shall require the
consent of at least fifty percent (50%) of the Participation Rights Holders,
Holders of Registrable Shares, as the case may be, required in such provision.

     No waivers of or exceptions to any term, condition or provision of this
Agreement, in any one or more instances, shall be deemed to be, or construed as,
a further or continuing waiver of any such term, condition or provision.

     4.5  Counterparts.  this Agreement may be executed in several counterparts,
          ------------
each of which shall be deemed an original, but all of which together shall
constitute one and the same instrument.

     4.6  Captions. The captions of the sections, subsections and paragraphs of
          --------
this Agreement have been added for convenience only and shall not be deemed to
be a part of this Agreement.

     4.7  Severability. Each provision of this Agreement shall be interpreted in
          ------------
such manner as to validate and give effect thereto to the fullest lawful extent,
but if any provision of this Agreement is determined by a court of competent
jurisdiction to be invalid or unenforceable under applicable law, such provision
shall be ineffective only to the extent so determined and such invalidity or
unenforceability shall not affect the remainder of such provision or the
remaining provisions of this Agreement.

     4.8  Governing Law. This Agreement shall be governed by and construed in
          --------------
accordance with the laws of the State of Delaware.

                                     * * *

                                      -18-
<PAGE>

     IN WITNESS WHEREOF, the parties have executed this Agreement as of the date
first above written.

                                     COMPANY
                                     -------

                                     INSPIRE PHARMACEUTICALS, INC.

                                     By:  /s/ Christy L. Shaffer
                                          --------------------------------------
                                          Christy L. Shaffer, Ph.D.
                                          President and Chief Executive Officer

                                     INVESTORS
                                     ---------

                                     DOMAIN PARTNERS III, L.P.
                                     BY: ONE PALMER SQUARE ASSOCIATES

                                     BY:    /s/ Kathleen K. Shoemaker
                                            ------------------------------------

                                     NAME:  Kathleen K. Shoemaker
                                            ------------------------------------

                                     TITLE: General Partner
                                            ------------------------------------

                                     DP III ASSOCIATES, L.P.
                                     BY: ONE PALMER SQUARE ASSOCIATES

                                     BY:    /s/ Kathleen K. Shoemaker
                                            ------------------------------------

                                     NAME:  Kathleen K. Shoemaker
                                            ------------------------------------

                                     TITLE: General Partner
                                            ------------------------------------
<PAGE>

                                     BIOTECHNOLOGY INVESTMENTS LIMITED
                                     BY: OLD COURT LIMITED

                                     BY:    /s/ Kathleen K. Shoemaker
                                            ------------------------------------

                                     NAME:  Kathleen K. Shoemaker
                                            ------------------------------------

                                     TITLE: Attorney-In-Fact
                                            ------------------------------------

                                     ALTA V LIMITED PARTNERSHIP
                                     BY: ALTA V MANAGEMENT PARTNERS, L.P.

                                     BY:    /s/ Eileen McCarthy
                                            ------------------------------------

                                     NAME:  Eileen McCarthy
                                            ------------------------------------

                                     TITLE: General Partner
                                            ------------------------------------

                                     CUSTOMS HOUSE PARTNERS

                                     BY:    /s/ Eileen McCarthy
                                            ------------------------------------

                                     NAME:  Eileen McCarthy
                                            ------------------------------------

                                     TITLE: General Partner
                                            ------------------------------------

                                     MEDICAL SCIENCE PARTNERS II, L.P.

                                     BY:    /s/ Joseph F. Lovett
                                            ------------------------------------

                                     NAME:  Joseph F. Lovett
                                            ------------------------------------

                                     TITLE: General Partner
                                            ------------------------------------
<PAGE>

                           INTERSOUTH PARTNERS III, L.P.

                           BY:    /s/ Dennis J. Dougherty
                                  ---------------------------------------------

                           NAME:  Dennis J. Dougherty
                                  ---------------------------------------------

                           TITLE: General Partner Intersouth Associates II, L.P.
                                  ----------------------------------------------

                           MSP II CO-INVESTMENT L.P.

                           BY:    /s/ Joseph F. Lovett
                                  ---------------------------------------------

                           NAME:  Joseph F. Lovett
                                  ---------------------------------------------

                           TITLE: General Partner
                                  ----------------------------------------------

                           VIKING MEDICAL VENTURES LIMITED

                           BY:    /s/ Graeme A. Witts
                                  ----------------------------------------------

                           NAME:  Graeme A. Witts
                                  ----------------------------------------------

                           TITLE: Director
                                  ----------------------------------------------

                           ACTA FINANCE

                           BY:    /s/ George Muller
                                  ----------------------------------------------

                           NAME:  George Muller
                                  ----------------------------------------------

                           TITLE: Director
                                  ----------------------------------------------
<PAGE>

                                COMDISCO, INC.

                                BY:    /s/ James Labe
                                       -----------------------------------------

                                NAME:  James Labe
                                       -----------------------------------------

                                TITLE: President, ComdiscoVentures
                                       -----------------------------------------

                                ALIMENTARIA INTERNATIONAL, INC.

                                BY:    /s/ George Muller
                                       -----------------------------------------

                                NAME:  George Muller
                                       -----------------------------------------

                                TITLE: Power-of-Attorney
                                       -----------------------------------------

                                LANDMARK EQUITY PARTNERS V, L.P.

                                BY:_____________________________________________

                                NAME:___________________________________________

                                TITLE:__________________________________________

                                LANDMARK SECONDARY PARTNERS, L.P.

                                BY:_____________________________________________

                                NAME:___________________________________________

                                TITLE:__________________________________________
<PAGE>

                                UEMCO XI LIMITED PARTNERSHIP

                                BY:    /s/ Joseph F. Lovett
                                       -----------------------------------------

                                NAME:  Joseph F. Lovett
                                       -----------------------------------------

                                TITLE: General Partner
                                       -----------------------------------------

                                EAGLE CONSTELLATION FUND LTD.

                                BY:    /s/ Joseph F. Lovett
                                       -----------------------------------------

                                NAME:  Joseph F. Lovett
                                       -----------------------------------------

                                TITLE: General Partner
                                       -----------------------------------------

                                BEACON HILL FINANCIAL

                                BY:    /s/ Robert F. Johnston
                                       -----------------------------------------

                                NAME:  Robert F. Johnston
                                       -----------------------------------------

                                TITLE: President
                                       -----------------------------------------

                                MEDICAL SCIENCE II CO-INVESTMENT L.P.

                                BY: ____________________________________________

                                NAME:___________________________________________

                                TITLE:__________________________________________
<PAGE>

                                NORAM TRUST

                                BY:    /s/ James P. Conroy
                                       -----------------------------------------

                                NAME:  James P. Conroy
                                       -----------------------------------------

                                TITLE: Trustee
                                       -----------------------------------------

                                AL-MIDANI INVESTMENT COMPANY LIMITED

                                BY:    /s/ Mhd. Nabil Al-Midani
                                       -----------------------------------------

                                NAME:  Mhd. Nabil Al-Midani
                                       -----------------------------------------

                                TITLE: Director
                                       -----------------------------------------

                                GUTRAFIN LIMITED

                                BY:    /s/ F.C. Lang
                                       -----------------------------------------

                                NAME:  F.C. Lang
                                       -----------------------------------------

                                TITLE: Senior Investment Representative
                                       -----------------------------------------

                                CHILD HEALTH INVESTMENT CORPORATION

                                BY:    /s/ Craig F. Fischer
                                       -----------------------------------------

                                NAME:  Craig F. Fischer
                                       -----------------------------------------

                                TITLE: COO
                                       -----------------------------------------
<PAGE>

                                VAUGHN BRYSON

                                BY:    /s/ Vaughn Bryson
                                       -----------------------------------------

                                NAME:  Vaughn Bryson
                                       -----------------------------------------

                                TITLE: _________________________________________

                                FARVIEW MANAGEMENT COMPANY, L.P.

                                BY:    /s/ Judith E. Cook
                                       -----------------------------------------

                                NAME:  Judith E. Cook
                                       -----------------------------------------

                                TITLE: General Partner
                                       -----------------------------------------

                                MSP HEALTHCARE OPPORTUNITIES INVESTMENT POOL

                                BY:    /s/ F.C. Lang
                                       -----------------------------------------

                                NAME:  F.C. Lang
                                       -----------------------------------------

                                TITLE: CEO
                                       -----------------------------------------

                                ROY M. BARBEE

                                BY:_____________________________________________

                                NAME:___________________________________________

                                TITLE:__________________________________________
<PAGE>

                                BENEFIT CAPITAL MANAGEMENT CORP. AS INVESTMENT
                                MANAGER FOR THE PRUDENTIAL INSURANCE COMPANY OF
                                AMERICA SEPARATE ACCOUNT NO. VCA-GA-5298

                                BY:    /s/ Sue DeCarlo
                                       -----------------------------------------

                                NAME:  Sue DeCarlo
                                       -----------------------------------------

                                TITLE: Sr. VP & CEO
                                       -----------------------------------------

                                NMT NEW MEDICAL TECHNOLOGIES

                                BY:    /s/ J.F. Rejeange   /s/ J.F. Geigy
                                       -----------------------------------------

                                NAME:  J.F. Rejeange      J.F. Geigy
                                       -----------------------------------------

                                TITLE: Attorney-In-Fact   Attorney-In-Fact
                                       -----------------------------------------

                                JAFCO CO. LTD.

                                BY:    /s/ Mitsumasa Murase
                                       -----------------------------------------

                                NAME:  Mitsumasa Murase
                                       -----------------------------------------

                                TITLE: President
                                       -----------------------------------------

                                JAFCO R-3 INVESTMENT ENTERPRISE PARTNERSHIP

                                BY:    /s/ Mitsumasa Murase
                                       -----------------------------------------

                                NAME:  Mitsumasa Murase
                                       -----------------------------------------

                                TITLE: President, Its Executive Partner
                                       -----------------------------------------
<PAGE>

                                JAFCO JS-3 INVESTMENT ENTERPRISE PARTNERSHIP

                                BY:    /s/ Mitsumasa Murase
                                       -----------------------------------------

                                NAME:  Mitsumasa Murase
                                       -----------------------------------------

                                TITLE: President, Its Executive Partner
                                       -----------------------------------------

                                JAFCO G-6(A)

                                BY:    /s/ Mitsumasa Murase
                                       -----------------------------------------

                                NAME:  Mitsumasa Murase
                                       -----------------------------------------

                                TITLE: President, Its Executive Partner
                                       -----------------------------------------

                                JAFCO G-6(B)

                                BY:    /s/ Mitsumasa Murase
                                       -----------------------------------------

                                NAME:  Mitsumasa Murase
                                       -----------------------------------------

                                TITLE: President, Its Executive Partner
                                       -----------------------------------------

                                JAFCO G-7(A)

                                BY:    /s/ Mitsumasa Murase
                                       -----------------------------------------

                                NAME:  Mitsumasa Murase
                                       -----------------------------------------

                                TITLE: President, Its Executive Partner
                                       -----------------------------------------
<PAGE>

                                JAFCO G-7(B)

                                BY:    /s/ Mitsumasa Murase
                                       -----------------------------------------

                                NAME:  Mitsumasa Murase
                                       -----------------------------------------

                                TITLE: President, Its Executive Partner
                                       -----------------------------------------

                                FUJIGIN CAPITAL CO.

                                BY:    /s/ Osami Kita
                                       -----------------------------------------

                                NAME:  Osami Kita
                                       -----------------------------------------

                                TITLE: President
                                       -----------------------------------------

                                CURRAN PARTNERS, L.P.

                                BY:    /s/ John P. Curran
                                       -----------------------------------------

                                NAME:  John P. Curran
                                       -----------------------------------------

                                TITLE: General Partner
                                       -----------------------------------------

                                DELAWARE CHARTER AND TRUST, JOHN P. CURRAN, IRA

                                BY:    /s/ John P. Curran
                                       -----------------------------------------

                                NAME:  John P. Curran
                                       -----------------------------------------

                                TITLE: Owner
                                       -----------------------------------------
<PAGE>

                                INTERWEST PARTNERS VII, L.P.
                                INTERWEST INVESTORS VII, L.P.

                                BY:    InterWest Management Partners VII, LLC,
                                       their General Partner

                                BY:    /s/ Rodney A. Ferguson
                                       -----------------------------------------
                                       Venture Member

                                GC&H INVESTMENTS

                                BY:    /s/ John L. Cardoza
                                       -----------------------------------------

                                NAME:  John L. Cardoza
                                       -----------------------------------------

                                TITLE: Executive Partner
                                       -----------------------------------------

                                GENENTECH, INC

                                BY:    /s/ Arthur D. Levinson
                                       -----------------------------------------

                                NAME:  Arthur D. Levinson, Ph.D.
                                       -----------------------------------------

                                TITLE: President and Chairman of the Board
                                       -----------------------------------------
<PAGE>

                      SCHEDULE 1 - SCHEDULE OF INVESTORS
                      ----------------------------------

         SERIES A INVESTORS
         ------------------

         DOMAIN PARTNERS III, L.P.
         One Palmer Square
         Suite 515
         Princeton, NJ 08542
         Attention: Jesse I. Treu, Partner
         Fax: (609) 683-9789

         DP III ASSOCIATES, L.P.
         One Palmer Square
         Suite 515
         Princeton, NJ 08542
         Attention: Jesse I. Treu, Partner
         Fax: (609) 683-9789

         OLD COURT LIMITED AS NOMINEE OF
         BIOTECHNOLOGY INVESTMENTS LIMITED
         St. Peter Port House
         Sausmarez Street
         St. Peter Port, Guernsey
         Channel Islands

         with a copy to:
         Domain Partners
         One Palmer Square
         Suite 515
         Princeton, NJ
         Fax: (609) 683-9789

         ALTA V LIMITED PARTNERSHIP
         c/o Burr, Egan Deleage and Co.
         One Post Office Square, Suite 3800
         Boston, MA 02110
         Attention: Eileen McCarthy
         Fax: (617) 482-1944
<PAGE>

         CUSTOMS HOUSE PARTNERS
         c/o Burr, Egan Deleage and Co.
         One Post Office Square, Suite 3800
         Boston, MA 02110
         Attention: Eileen McCarthy
         Fax: (617) 482-1944

         MSP II CO-INVESTMENT L.P.
         161 Worcester Road, Suite 301
         Framingham, MA 01701
         Attention: Joseph Lovett
         General Partner and Joseph Lovett,
         General Partner
         Fax: (508) 620-9251

         LANDMARK EQUITY PARTNERS V, L.P.
         760 Hopmeadow Street
         Simsbury, CT 06070
         Attention: Anthony J. Rosigno

         LANDMARK SECONDARY PARTNERS, L.P.
         760 Hopmeadow Street
         Simsbury, CT 06070
         Attention: Anthony J. Rosigno

         ACTA FINANCE
         Avenue Montbenon 2
         Lausanne, Switzerland 1003
         Attention: Georges Muller
         Fax: 011-41-21-320-7454

         ALIMENTARIA INTERNATIONAL, INC.
         Avenue Montbenon 2
         Lausanne, Switzerland 1003
         Attention: Georges Muller
         Fax: 011-41-21-320-7454

         VIKING MEDICAL VENTURES LIMITED
         8 Queensway House
         Queen Street
         St. Helier, Jersey JE24WD
         Attention: Michael Edmonds, Director
         Fax: 011-44-534-69770
<PAGE>

         INTERSOUTH PARTNERS III L.P.
         3211 Shannon Road, Suite 610
         Durham, N.C. 27707
         Attention: Dennis J. Dougherty, General Partner
         Fax: (919) 493-6649

         COMDISCO, INC.
         6111 North River Road
         Rosemont, IL 60018
         Attention: Jill Hanses
         Fax: 847-518-5465

         MEDICAL SCIENCE PARTNERS II, L.P.
         161 Worcester Road, Suite 301
         Framingham, MA 01701
         Attention: Joseph Lovett
         Fax: (508) 620-9251

         SERIES B INVESTORS
         ------------------

         UEMCO XI LIMITED PARTNERSHIP
         c/o Joseph Lovett
         c/o Medical Science Partners
         161 Worcester Road, Suite 301
         Framingham, MA 01701
         Fax: (508) 620-9251

         EAGLE CONSTELLATION FUND LTD.
         c/o Joseph Lovett
         c/o Medical Science Partners
         161 Worcester Road, Suite 301
         Framingham, MA 01701
         Fax: (508) 620-9251

         BEACON HILL FINANCIAL
         c/o Mr. Jim O'Brien
         19 Elm Street
         Cohasset, MA 02025
<PAGE>

         INTERSOUTH PARTNERS III L.P.
         One Copley Parkway Suite 101
         Morrisville, North Carolina 27560
         Attention: Dennis J. Dougherty,
         General Partner
         Fax: (919) 544-6645

         COMDISCO, INC.
         6111 North River Road
         Rosemont, IL 60018
         Attention: Jill Hanses
         Fax: 847-518-5465

         NORAM TRUST
         c/o James P. Conroy
         c/o Windels, Marx, Davies & Ives
         56 West 56/th/ Street
         New York N.Y. 10019

         AL-MIDANI INVESTMENT COMPANY LIMITED
         P.O. Box 40761
         Riyadh, Saudi Arabia 11511
         Attn: Mr. Nabil Al-Midani
         (registered office: P.O. Box 1111, Grand Cayman
         Cayman Islands, B.W.I.)

         CHILD HEALTH INVESTMENT CORPORATION
         6803 West 64/th/ Street
         Shawnee Mission, KS 66202
         Attention: Craig Fischer
         Fax: 913-262-1575

         VAUGHN BRYSON
         Life Science Advisors, Inc.
         7225 Woodland Drive
         Suite 230
         Indianapolis, IN 46278

         ROY M. BARBEE
         Life Science Advisors, Inc.
         7225 Woodland Drive
         Suite 230
         Indianapolis, IN 46278
<PAGE>

         FARVIEW MANAGEMENT COMPANY, L.P.
         26 Timber Park Drive
         Black Mountain, N.C. 28711
         Attention: Joseph Cook, Jr., General Partner

         MSP HEALTHCARE OPPORTUNITIES INVESTMENT POOL
         c/o Gutrafin
         40 Egerton Crescent
         London, SW3 2EB
         UNITED KINGDOM
         Attention: Francis Lang
         Fax: 011-71-823-7046

         MEDICAL SCIENCE II CO-INVESTMENT L.P.
         c/o Medical Science Partners
         161 Worcester Road, Suite 301
         Framingham, MA 01701
         Attention: Joseph Lovett
         Fax: (508) 620-9251

         BENEFIT CAPITAL MANAGEMENT CORP. AS
         INVESTMENT MANAGER FOR THE PRUDENTIAL
         INSURANCE COMPANY OF AMERICA
         SEPARATE ACCOUNT NO. VCA-GA-5298
         34 Old Ridgebury Road
         Danbury, CT 06817
         Attention: Susan DeCarlo

         NMT NEW MEDICAL TECHNOLOGIES
         Innovation Center
         Gewerbestrasse 18
         Allschwil, CH-4123
         SWITZERLAND
         Attention: Lucas Alioth

         JAFCO CO. LTD.
         Tekko Building, 1-8-2 Marunouchi,
         Chiyoda-ku, Tokyo
         JAPAN 100
         Attention: Mitsumasa Murase, President

         JAFCO R-3 INVESTMENT ENTERPRISE PARTNERSHIP
         Tekko Building, 1-8-2 Marunouchi,
         Chiyoda-ku, Tokyo
         JAPAN 100
         Attention: Mitsumasa Murase, President
<PAGE>

         JAFCO JS-3 INVESTMENT ENTERPRISE PARTNERSHIP
         Tekko Building, 1-8-2 Marunouchi,
         Chiyoda-ku, Tokyo
         JAPAN 100
         Attention: Mitsumasa Murase, President

         JAFCO G-6(A)
         Tekko Building, 1-8-2 Marunouchi,
         Chiyoda-ku, Tokyo
         JAPAN 100
         Attention: Mitsumasa Murase, President

         JAFCO G-6(B)
         Tekko Building, 1-8-2 Marunouchi,
         Chiyoda-ku, Tokyo
         JAPAN 100
         Attention: Mitsumasa Murase, President

         JAFCO G-7(A)
         Tekko Building, 1-8-2 Marunouchi,
         Chiyoda-ku, Tokyo
         JAPAN 100
         Attention: Mitsumasa Murase, President

         JAFCO G-7(B)
         Tekko Building, 1-8-2 Marunouchi,
         Chiyoda-ku, Tokyo
         JAPAN 100
         Attention: Mitsumasa Murase, President

         FUJIGIN CAPITAL CO.
         Central Plaza Building
         4/th/ Floor
         1-1 Kaguragasi, Shinjuku-ku
         Tokyo, 162
         JAPAN
         Attention: Kazuko Murata

         DOMAIN PARTNERS III, L.P.
         One Palmer Square
         Suite 515
         Princeton, NJ 08542
         Attention: Jesse I. Treu, Partner
         Fax: (609) 683-9789
<PAGE>

         DP III ASSOCIATES, L.P.
         One Palmer Square
         Suite 515
         Princeton, NJ 08542
         Attention: Jesse I. Treu, Partner
         Fax: (609) 683-9789

         OLD COURT LIMITED AS NOMINEE OF
         BIOTECHNOLOGY INVESTMENTS LIMITED
         St. Peter Port House
         Sausmarez Street
         St. Peter Port, Guernesy
         Channel Islands

         with a copy to:
         Domain Partners
         One Palmer Square
         Suite 515
         Princeton, NJ
         Fax: (609) 683-9789

         ALIMENTARIA INTERNATIONAL, INC.
         Avenue Montbenon 2
         Lausanne, Switzerland 1003
         Attention: Georges Muller
         Fax: 011-41-21-320-7454

         VIKING MEDICAL VENTURES LIMITED
         8 Queensway House
         Queen Street
         St. Helier, Jersey JE24WD
         Attention: Michael Edmonds, Director
         Fax: 011-44-534-69770

         ALTA V LIMITED PARTNERSHIP
         c/o Burr, Egan Deleage and Co.
         One Post Office Square, Suite 3800
         Boston, MA 02110
         Attention: Eileen McCarthy
         Fax: (617) 482-1944
<PAGE>

         CUSTOMS HOUSE PARTNERS
         c/o Burr, Egan Deleage and Co.
         One Post Office Square, Suite 3800
         Boston, MA 02110
         Attention: Eileen McCarthy
         Fax: (617) 482-1944

         MEDICAL SCIENCE PARTNERS II, L.P.
         161 Worcester Road, Suite 301
         Framingham, MA 01701
         Attention: Joseph Lovett
         Fax: (508) 620-9251

         SERIES E INVESTORS
         ------------------

         DOMAIN PARTNERS III, L.P.
         One Palmer Square
         Suite 515
         Princeton, NJ 08542
         Attention: Jesse I. Treu, Partner
         Fax: (609) 683-9789

         OLD COURT LIMITED AS NOMINEE OF
         BIOTECHNOLOGY INVESTMENTS LIMITED
         St. Peter Port House
         Sausmarez Street
         St. Peter Port, Guernesy
         Channel Islands

         with a copy to:
         Domain Partners
         One Palmer Square
         Suite 515
         Princeton, NJ
         Fax: (609) 683-9789

         FARVIEW MANAGEMENT COMPANY, L.P.
         26 Timber Park Drive
         Black Mountain, N.C. 28711
         Attention: Joseph Cook, Jr., General Partner
<PAGE>

         BENEFIT CAPITAL MANAGEMENT CORP. AS
         INVESTMENT MANAGER FOR THE PRUDENTIAL
         INSURANCE COMPANY OF AMERICA
         SEPARATE ACCOUNT NO. VCA-GA-5298
         34 Old Ridgebury Road
         Danbury, CT 06817
         Attention: Susan DeCarlo

         CUSTOMS HOUSE PARTNERS
         c/o Burr, Egan Deleage and Co.
         One Post Office Square, Suite 3800
         Boston, MA 02110
         Attention: Eileen McCarthy
         Fax: (617) 482-1944

         NMT NEW MEDICAL TECHNOLOGIES
         Innovation Center
         Gewerbestrasse 18
         Allschwil, CH-4123
         SWITZERLAND
         Attention: Lucas Alioth

         NORAM TRUST
         c/o James P. Conroy
         c/o Windels, Marx, Davies & Ives
         56 West 56/th/ Street
         New York N.Y. 10019

         AL-MIDANI INVESTMENT COMPANY LIMITED
         P.O. Box 40761
         Riyadh, Saudi Arabia  11511
         Attn: Mr. Nabil Al-Midani
         (registered office: P.O. Box 1111, Grand Cayman
         Cayman Islands, B.W.I.)

         ALTA V LIMITED PARTNERSHIP
         c/o Burr, Egan Deleage and Co.
         One Post Office Square, Suite 3800
         Boston, MA 02110
         Attention: Eileen McCarthy
         Fax: (617) 482-1944

         GUTRAFIN LIMITED
         MSP Healthcare Opportunities
         Investment Pool, c/o Gutrafin
<PAGE>

         40 Egerton Crescent
         London, SW3 2EB
         UNITED KINGDOM
         Attention: Francis Lang

         CURRAN PARTNERS, L.P.
         Curran Capital
         237 Park Avenue, Suite 900
         New York, N.Y. 10017
         Attention: John Curran

         DELAWARE CHARTER AND TRUST,
         JOHN P. CURRAN, IRA
         237 Park Avenue, Suite 900
         New York, N.Y. 10017
         Attention: John Curran

         InterWest Partners VII, L.P.
         3000 Sand Hill Road
         Building 3, Suite 255
         Menlo Park, California 94025
         Attention: Rodney Ferguson
         Fax: (650) 854-4706

         InterWest Investors VII, L.P.
         3000 Sand Hill Road
         Building 3, Suite 255
         Menlo Park, California 94025
         Attention: Rodney Ferguson
         Fax: (650) 854-4706

         GC&H Investments
         c/o John Cardoza
         One Maritime Plaza
         20th Floor
         San Francisco, CA 94111
         Fax: (415) 951-3699

         SERIES G INVESTOR
         -----------------

         Genentech, Inc.
         1 DNA Way
         South San Francisco, California 94808
         Attention: Corporate Secretary
         Facsimile No.: (650) 952-9881

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