<PAGE>

                                                       CERTAIN CONFIDENTIAL
                                                       MATERIAL CONTAINED IN
                                                       THIS DOCUMENT, MARKED BY
                                                       BRACKETS, HAS BEEN
                                                       OMITTED AND FILED
                                                       SEPARATELY WITH THE
                                                       SECURITIES AND EXCHANGE
                                                       COMMISSION PURSUANT TO
                                                       RULE 24b-2 OF THE
                                                       SECURITIES EXCHANGE ACT
                                                       OF 1934, AS AMENDED.


                                SECOND AMENDMENT

     This constitutes the Second Amendment to the Research, Development and
License Agreement (the "Agreement") entered into between Ono Pharmaceutical Co.,
Ltd., ("Ono") and Cortech, Inc., ("Cortech") as of March 8, 1995. The provisions
of this Second Amendment shall become effective upon its completed execution.

     Whereas, Ono and Cortech wish to modify certain provisions of the
Agreement, including the First Amendment, in order to facilitate their
collaboration and better serve the accomplishment of their mutual objectives,

     Now, Therefore, in consideration of the foregoing, Ono and Cortech agree
that the Agreement is hereby modified by incorporation of the following provided
additions, changes and deletions:

     1.   The First Amendment is entirely superseded and replaced by this Second
Amendment, and, accordingly, subsequent to such time as this Second Amendment
becomes effective as provided herein, the First Amendment shall have no further
operation or effect.

     2.   The definition of "BACK-UP COMPOUND" as previously operative under the
Agreement is understood and agreed to be removed from the Agreement, along with
all instances of that term's employment in connection with the Agreement as
formerly provided under the First Amendment.

     3.   The definition of "CORTECH KNOW-HOW" as previously operative under the
Agreement is superseded and replaced by the following new definition:

     "CORTECH KNOW-HOW" shall mean any information or data not otherwise
generally known which are necessary for Ono to manufacture, use, develop, sell
or seek approval to market any Licensed Compound, including but not limited to
Developed Compound, as an ingredient of Products, in which Cortech has an
ownership or licensable interest, all as is presently in the possession of
Cortech and which may come into Cortech's possession prior to any completion,
termination or other cessation of the Project.

     4.   The definition of "CORTECH PATENT RIGHTS" as previously operative
under the Agreement is superseded and replaced by the following new definition:

     "CORTECH PATENT RIGHTS" shall mean (i) all U.S. and foreign patents and
patent applications which contain claims covering or directed to any Licensed
Compound, including but not limited to Developed Compound, which are owned by
Cortech as sole or joint owner or under which Cortech has licensable rights as
of the Effective Date, or as of the completion, termination or other cessation
of the Project, as the case may be, and (ii) any division, continuation or
continuation-in-part of any such patents and patent


                                        1
<PAGE>


applications, including any reissue, reexamination or extension of the patent,
any extended or restored term, and any confirmation patent, registration patent
or addition.

     5.   The definition of "DEVELOPED COMPOUND" as previously operative under
the Agreement is superseded and replaced by the following new definition:

     "DEVELOPED COMPOUND" shall mean (i) the orally active NEI, developed in
accordance with and within the specified scope of the Project, to be accepted
for further development by Ono from among Licensed Compounds at the conclusion
of the Project, or, in the alternative, (ii) a Licensed Compound that Ono has
formally elected, as herein provided, to designate as Developed Compound in
substitution for a previously designated Developed Compound.

     6.   "LICENSED COMPOUND" shall mean any particular orally active NEI,
discovered in accordance with and within the specified scope of the Project,
that (i) substantially satisfies the criteria developed by the Evaluation
Committee to identify appropriate candidates for selection as a Developed
Compound, and (ii) Ono formally elects to designate as such by notice to Cortech
at any time during the Project or within ninety (90) days following conclusion
of the Project.

     7.   The definition of "PRODUCT" as previously operative under the
Agreement is superseded and replaced by the following new definition:

     "PRODUCT" shall mean any pharmaceutical preparation in a finished packaged
dosage form suitable for oral administration to patients that contains any
Licensed Compound as the sole active ingredient or that contains an approved-as-
safe mixture of any Licensed Compound along with one or more other
therapeutically active ingredients first approved as safe and effective for use
in single formulation.

     8.   Article 3.2 of the Agreement, under the heading "Cortech's Reporting
Responsibility", is hereby modified in its entirety as follows:

     During the first two years of the Project, Cortech shall provide Ono with
(i) a quarterly progress report of the Project within thirty (30) days after the
end of each quarter during the term of the Project, beginning with the
completion of the first quarter after the Project Commencement Date and (ii) an
annual report of the Project, which may also serve in lieu of a separate
quarterly report hereunder with respect to the last quarter its period includes,
within thirty (30) days after each anniversary of the Project Commencement Date
during the term of the Project.

     During the third year of the Project, Cortech shall provide Ono with (i) a
research report of the Project within thirty (30) days after termination of
Cortech's research responsibilities as delineated in Exhibit A and (ii) an
overall final research report within thirty (30) days after termination of the
Project.  Such reports shall include information detailing basic progress of the
Project in the context of the prepared Project Goals set forth in Exhibit A, and
shall include disclosure of the chemical structures of compounds newly
synthesized by Cortech pursuant to the Project to the extent Cortech has
completed IN VITRO


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and IN VIVO testing of such new compounds at the time of a report's preparation.
Such overall final research report shall include information detailing, if any,
additional research work performed by Cortech with regard to orally active NEIs
beyond the period of its research responsibilities during the term of the
Project.  Ono shall provide Cortech with an overall final research report within
thirty (30) days after termination of the Project.  This report shall include
information detailing basic progress of the Project in the context of the
prepared Project Goals set forth in Exhibit A and will include disclosure of the
chemical structures of compounds newly synthesized by Ono reflecting
modifications made by Ono based on or relating to Cortech Know-how or Cortech
Patent Rights.  During the first two years of the Project, Cortech shall also
submit to Ono an annual statement of account within thirty (30) days after the
end of each calendar year.  During the third year of the Project, Cortech shall
submit to Ono a statement of account within thirty (30) days after the end of
Cortech's research responsibilities as outlined in Exhibit A.  All reports by
Cortech to Ono and Ono to Cortech, as well as oral and written disclosures by
Cortech in connection with the subject matter of such reports, shall be subject
to the provisions of Article 6.

     9.   Article 4.1 of the Agreement, under the heading "License", is hereby
modified to provide in its entirety as follows:

          (a)  Subject without qualification to the limited term provided in
Article 4.1(c) as applicable with respect to all Licensed Compounds other than
Developed Compound, Cortech grants to Ono an exclusive, royalty-free,
nontransferable license within the Territory, with the right to grant
sublicenses, under Cortech Know-how and Cortech Patent Rights to make, have
made, use and sell any Licensed Compound as  an ingredient of  Products to be
developed by Ono in the Territory. The term of such license is subject to
termination as provided in this Agreement; provided, however, that, unless and
except as earlier terminated by application of the provisions of this Agreement,
with respect to Developed  Compound as finally identified at the conclusion of
the Alternative Selection Period hereinafter defined such license shall become a
perpetual, exclusive, and fully paid-up license after expiration of all issued
and pending Cortech Patent Rights (i.e., after expiration of all patents within
Cortech Patent Rights that have issued).  It is understood and agreed that,
while Ono shall possess certain rights permitting the substitution of a Licensed
Compound as Developed Compound in place of a previously designated Developed
Compound pursuant to Article 4.1(b), in no event shall more than one compound be
simultaneously designated as a Developed Compound.

          (b)  Upon the condition that Ono first designates a Developed Compound
from among Licensed Compounds by its acceptance of such compound for further
development beyond the Project, for a period of three years following expiration
of the three year term of the Project (the "Alternative Selection Period"), Ono
shall have the right upon its sole election to substitute any other Licensed
Compound as Developed Compound hereunder in the place of the previously
designated Developed Compound. No payment beyond the funding provided under this
Agreement shall be required of Ono in order to effect such election. During the
Alternative Selection Period, Cortech shall not grant to any third party in the
Territory any rights or license to develop or commercialize as pharmaceutical
products any NEI that is discovered in accordance with and within the scope of
the Project.


                                        3
<PAGE>


          (c)  The term of the license granted hereinabove as applicable to
Licensed Compound(s), other than the finally designated Developed Compound,
shall terminate in all respects at the conclusion of the Alternative Selection
Period, subsequent to which time only Developed Compound as such is designated
at the conclusion of the Alternative Selection Period shall continue as subject
to the license granted by provision of this Article 4, unless and except as such
may otherwise be terminated.

      10. Article 4.3 of the Agreement, under the heading "Ono's Preclinical
Data", is hereby modified to provide in its entirety as follows:

     Ono shall, upon Cortech's request, make available to Cortech preclinical
data and other information that Ono develops or shall come to possess in
relation to any Licensed Compound, including but not limited to Developed
Compound, and/or Product(s), and Cortech shall have the right to use such
preclinical data and other information in connection with the development,
registration and commercialization of Product(s) outside the Territory.  In the
event that Cortech and/or a Western Partner uses any preclinical data generated
by Ono pursuant to the Project, if and to the extent that such data contributes
to the development and/or registration of any Product in Europe and/or North
America by serving substantially in place of comparable data (and thereby
avoiding most of the expense that would otherwise necessarily have been incurred
had Cortech or its Western Partner generated such data) which Cortech or its
Western Partner would otherwise have been required to generate for the same
purpose; THEN Cortech will, at it sole option, either

          (a)  promptly following such use pay Ono [---*---] of the documented
reasonable and customary expenses incurred by Ono in generating the data used in
the manner described above, or

          (b)  subject to the following stated limitations, pay to Ono [---*---]
of amounts as and when received by Cortech from the Western Partner in the form
of license fees, milestone payments and/or royalties in relation to Product
rights in Europe and/or North America; PROVIDED HOWEVER, that

               (i)  Ono shall in no event be entitled to receive any portion of
amounts paid to Cortech by its Western Partner in consideration of, or
reimbursement for, expenses incurred, or to be incurred, by or on behalf of
Cortech, and

               (ii) the aggregate total of payments to Ono pursuant to this
Article IV shall not exceed the lesser of (i) [---*---] or (ii) [---*---] the
documented reasonable and customary expenses incurred by Ono in generating the
data used as described hereinabove.

     11.  Article 5.1 of the Agreement, under the heading "Ownership", is hereby
modified in its entirety to provide as follows:

          (a)  Cortech shall own the entire right, title and interest in all
inventions, discoveries, improvements and other technology, whether or not
patentable, made or conceived during the three year term of the Project by or
for Cortech, Ono or both (i)

                                               * CONIDENTIAL TREATMENT REQUESTED
                                        4
<PAGE>


within the scope of the Project or as a result of the Project, or (ii) based on
information disclosed in confidence to Ono by Cortech in connection with this
Agreement, and such inventions, discoveries, improvements and other technology
shall be considered a part of the Cortech Patent Rights or Cortech Know-how, as
the case may be.  Ono shall promptly disclose to Cortech the making, conception
or reduction to practice of any invention, discovery, improvement or other
technology made or conceived by or for Ono that is subject to the provision of
this Article 5.1(a), and all such inventions, discoveries, improvements and
other technologies shall be assigned to Cortech as reasonably requested to
effectuate the purpose of this article.  For the purpose of applying this
Article 5.1(a), it is understood that inventions, discoveries, improvements or
other technology made or conceived by or for Ono outside the scope of and not
resulting from the Project shall not be deemed to have been based on information
disclosed to Ono in confidence by Cortech in connection with this Agreement if
Ono can prove by contemporaneous, written records that such invention,
discovery, improvement or other technology was so made or conceived based solely
on information already known to Ono prior to the receipt by Ono of such
information from Cortech.  In the event Cortech discloses information to Ono in
confidence which Ono already possesses other than through disclosure from
Cortech, Ono will promptly notify Cortech of such prior possession and, upon
request, provide its documented verification thereof.

          (b)  Subject to the provision of Article 5.1(a), Ono shall own the
entire right, title and interest in all discoveries, improvements and other
technology, whether or not patentable, made or conceived solely by or for Ono
based on its own patent rights, know-how or other confidential information.

          (c)  Ono shall promptly disclose to Cortech any improvement or
modification which Ono may make to any Licensed Compound(s), including Developed
Compound, or to any other compound that incorporates or is based on structures
or other information disclosed by Cortech to Ono in connection with this
Agreement. In the event Ono, independently of Cortech and subsequent to the term
of the Project, first makes such improvement or modification, ownership of any
proprietary interest therein shall be jointly held by Ono and Cortech, and Ono
shall have exclusive rights to make, use and sell such improved or modified
compound (the "Improved Compound") in the Territory, and Cortech and/or its
Western Partner shall have exclusive rights to make, use and sell the Improved
Compound outside the Territory. Cortech shall reasonably compensate Ono for
Cortech's sale of product(s) containing Improved Compound which is covered by a
patent claiming Ono's improvement or modification, other than such claim as
shall be included within Cortech Patent Rights, provided, however, that it is
understood and agreed between the parties that such compensation shall not
become due with respect to any improvement or modification conceived during the
term of the Project, and, provided further, that rights to any such improvement
or modification conceived during the term of the Project shall be deemed to have
arisen within the scope of the Project and, therefore, be subject to the
provision of Article 5.1(a).  Any compensation to which Ono makes a proper claim
under this provision shall be determined on the basis of good faith negotiations
taking into account the nature and expense of Ono's contribution to the
improvement or modification.

          (d)  Neither party shall be obligated to engage in any joint
improvement


                                        5
<PAGE>


or inventive or discovery activity with the other, or devote any resources that
may otherwise lead to joint inventions, discoveries, improvements or other
technology.

     12.  Article 5.2 of the Agreement, under the heading "Patent Prosecution",
is hereby modified to provide in its entirety as follows:

          (a)  As long as it remains commercially justifiable, Cortech shall
prepare, file, prosecute and maintain in the Territory those Cortech Patent
Rights subject to the license granted to Ono under Article 4.1 above. If Cortech
determines that it is no longer commercially justifiable to so prepare, file,
prosecute or maintain any particular Cortech Patent Rights, Cortech shall
consult with Ono regarding same. Ono shall be copied on relevant correspondence
between Cortech and its patent attorneys with respect to preparation,
prosecution and maintenance of such patent applications filed in the Territory,
and in return, Ono shall provide to Cortech relevant data concerning preclinical
and clinical development of Products in accordance with Article 3.4 above and
advice with respect to filing, prosecution and maintenance of patent
applications in the Territory as reasonably requested by Cortech to assist in
successful prosecution and maintenance of Cortech Patent Rights. As long as Ono
retains exclusive and royalty-free rights to the license granted in Article 4.1
in the Territory, Ono shall reimburse Cortech for all reasonable expenses
incurred by Cortech in association with the patents and patent applications of
the Cortech Patent Rights which specifically cover the Licensed Compounds. Such
reimbursement by Ono shall be made upon receipt from Cortech, after Ono's
selection of the Developed Compound at the conclusion of the Project, of an
itemized invoice specifying all expenses incurred for preparing, filing and
prosecuting patent applications as well as maintaining issued patents for
Licensed Compounds, including, but not limited to, Developed Compound.

          (b)  Except in circumstances where a valid assignment of this
Agreement has been effected subject to its Article 12, in the event of
Cortech's bankruptcy, liquidation or dissolution, other than such as may occur
in connection with a merger or consolidation with another company also as
provided in Article 12 of the Agreement, Ono shall have the right within the
Territory to undertake the filing of patent applications and to maintain the
patent rights for any invention, discovery or improvement made by Ono in
relation to the Licensed Compounds, including but not limited to Developed
Compound.

          (c)  For so long as Ono retains in good standing an exclusive and
royalty-free license in the Territory with respect to Licensed Compound(s) as
provided under Article 4.1 of the Agreement, Ono may register, as appropriate
with the Japanese Patent Office under Article 77 of  the Patent Law of Japan,
the Senyou Jissiken specifying such license under the Cortech Patent Rights, as
it is provided in Article 4.1, including the right to sublicense as therein
granted, and Cortech or its successor shall upon request sign legal documents
reasonably and appropriately required for such purposes. It is understood and
agreed that registration as provided above shall be maintained and be applicable
only as to the final Developed Compound after expiration of the Alternative
Selection Period, and that the registration permitted hereunder will in no
respect operate to expand Ono's rights under the Agreement or to effect
Cortech's rights or duties under the Agreement or otherwise in any manner that
might be detrimental to Cortech or its interests.


                                        6
<PAGE>


     13.  Article 5.3(d) of the Agreement, under the heading "Infringement by a
Third Party", is hereby modified to provide in its entirety as follows:

      If Cortech declines to bring suit, Ono may file an infringement action in
its name or on behalf of Cortech where necessary, at its own expense, and
Cortech shall give all reasonable assistance to Ono with respect to patent and
legal questions.  In such case, Ono shall be the sole recipient of the proceeds
of any recovery, provided that Ono shall indemnify Cortech against any
documented expenses or liabilities, incurred by Cortech, relating to the
relevant proceedings, excluding however any and all expenses or liabilities
relating to the defense by Cortech of any claim that may be brought against
Cortech in connection with such proceedings, but not excluding expenses and
liabilities associated with patent invalidity, infringement or enforceability
claims relating to any Licensed Compound, including but not limited to Developed
Compound, in the Territory.

     14.  Article 6.1 of the Agreement, under the heading "Confidential
Information", is hereby modified to provide in its entirety as follows:

     Subject to the exceptions provided in 6.2 below, (a) all Cortech Know-how,
all information that is proprietary to Cortech pursuant to Article 5.1, all
Cortech patent applications not otherwise publicly disclosed by Cortech, all
reports and related disclosures pursuant to Article 3.2, and all other
information which is identified as being confidential which is received by Ono
from Cortech, and (b) information which is also identified as confidential and
which is received by Cortech from Ono during the term of this Agreement, shall,
for a period of ten (10) years after termination of this Agreement, be
maintained in confidence by the recipient and shall not be (i) used by the
recipient except as expressly permitted by the terms of this Agreement or the
parties' further written agreement, or (ii) disclosed to any other person, firm,
or agency, governmental or private, without the prior written consent of the
other party.  In the case of information subject to this Article 6 that is or
becomes proprietary to Cortech by the provision of Article 5.1, Ono shall be
deemed to be the recipient with respect to such information as confidential
information for purposes of determining the application of the terms of this
Article 6.

     15.  Article 7.2(b) of the Agreement, appearing under the heading "Research
and Milestone Payments", is hereby modified to provide in its entirety as
follows:

     Unless earlier terminated as provided herein, Ono shall make the following
additional, nonrefundable payments to Cortech in support of the research to be
conducted by or on behalf of Cortech under this Agreement:

                               Date of Payment                   Payment
                               ---------------                   -------
          (i)     first anniversary of the Effective Date        $1,375,000
                  ("Second Year Commencement")

          (ii)    date six months after Second Year              $1,375,000
                  Commencement


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          (iii)   or before October 17, 1996                     $1,500,000

          (iv)    second anniversary of the Effective Date       $1,475,000
                  ("Third Year Commencement").


     16.  Article 7.3 of the Agreement, under the heading "Developed Compound
Identification Payment", is hereby deleted in its entirety.

     17.  Notwithstanding anything provided in the Agreement to the contrary,
Cortech shall have no responsibilities to perform research or development
activities related to or in connection with the Project subsequent to September
14, 1997.

     18.  Exhibit A of the Agreement pertaining to Cortech's Responsibilities,
under the heading "Year Three", is hereby modified in its entirety as follows:

          (a)  Continue additional work in the areas of discovery chemistry,
biochemistry and plasma level evaluation until September 14, 1997 to identify a
compound or series of compounds appropriate for more formal evaluation and
development.

          (b)  Cooperate reasonably and in good faith, at Ono's expense, to
support patent prosecution with respect to Licensed Compound(s), and candidates
for selection as Licensed Compounds, in the Territory.

     19.  Exhibit A of the Agreement, under the heading "Ono Responsibilities",
is hereby modified in its entirety as follows:

          (a)  Screen selected compounds with regard to IN VIVO biological
activity to identify a compound or series of compounds appropriate for more
formal evaluation and development

          (b)  Evaluate the identified compound or series of compounds with
regard to IN VIVO efficacy, pharmacology, pharmacokinetics, absorption,
distribution, metabolism, and excretion (ADME), and conduct preliminary
formulation and toxicology studies.

          (c)  Develop pilot- and commercial-scale chemistry for GLP,
toxicology, and other requirements.

     20.  It is understood and agreed between the parties that while Section 19
above describes the responsibilities of Ono as contemplated at the time of this
Second Amendment's execution, nevertheless Ono shall be permitted the use of its
reasonable and good faith judgment in determining the work it shall carry out
pursuant to achievement of the Project's objectives subsequent to the date upon
which the Second Amendment shall become effective, it being understood that the
continued progress of research must inform decisions regarding such work, and
that departures from plan may become warranted. In any case, Ono will proceed
diligently with work in connection with the Project, and will use its reasonable
best efforts to achieve the objectives of the Project. Ono will consult with


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Cortech regarding any departures from work under the Project as planned.

     21.  Exhibit A of the Agreement within the section headed "Staffing", is
hereby modified in its entirety as follows:

                             [                  ---*---            ]
Headcount              Ph.D.    R.A.      Ph.D.    R.A.      Ph.D.    R.A.

Synthetic Chemistry    [                  ---*---                     ]

Biochemistry           [                  ---*---                     ]

Pharmacology           [                  ---*---                     ]

Modeling               [                  ---*---                     ]

Project Management     [                  ---*---                     ]

Analytical Chemistry   [                  ---*---                     ]

BioPharmaceutics       [                  ---*---                     ]
                     -----------------------------------------------------
                       [                  ---*---                     ]

     22.  SECOND AMENDMENT. The Agreement and this Second Amendment, set forth
the entire agreement between the parties.  This Second Amendment shall upon
taking effect be incorporated into and made a part of the Agreement, superseding
and replacing in its entirety the First Amendment.  All other terms and
conditions of the Agreement shall continue in full force and effect, except, in
the event any conflict arises between this Second Amendment and the Agreement,
this Second Amendment shall take precedence.

     23.  COUNTERPARTS. This Second Amendment may be executed in two
counterparts, each of which shall be deemed an original, but all of which
together shall constitute one and the same instrument.

                                             * CONFIDENTIAL TREATMENT REQUESTED
                                        9
<PAGE>


     IN WITNESS WHEREOF, the parties hereto have caused this Second Amendment to
be executed by their duly authorized officers in duplicate originals, one
original to be retained by each party hereto.

CORTECH, INC.                              ONO PHARMACEUTICAL CO., LTD.

By /s/ Kenneth Lynn                        By  /s/ Kimiichiro Matsumoto
   -------------------------------------       ---------------------------------
   Mr. Kenneth R. Lynn,                        Mr. Kimiichiro Matsumoto,
   President and Chief Executive Officer       Managing Director, Research and
                                               Development Headquarters

Date    April 22, 1997                     Date   April 23, 1997


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