Novel antagonists of endothelin are described, as well as methods for the preparation and pharmaceutical compositions of the same, which are useful in treating elevated levels of endothelin, acute and chronic renal failure, hypertension, myocardial infarction, metabolic, endocrinological, neurological disorders, congestive heart failure, endotoxic shock, subarachnoid hemorrhage, arrhythmias, asthma, preeclampsia, Raynaud's disease, percutaneous transluminal coronary angioplasty or restenosis, angina, cancer, pulmonary hypertension, ischemic disease, gastric mucosal damage, ischemic bowel disease, and diabetes.

BACKGROUND OF THE INVENTION 
The present invention relates to novel antagonists of endothelin useful as 
pharmaceutical agents, to methods for their production, to pharmaceutical 
compositions which include these compounds and a pharmaceutically 
acceptable carrier, and to pharmaceutical methods of treatment. More 
particularly, the novel compounds of the present invention are antagonists 
of endothelin useful in treating elevated levels of endothelin, acute and 
chronic renal failure, hypertension, myocardial infarction, metabolic, 
endocrinological, neurological disorders, congestive heart failure, 
endotoxic shock, subarachnoid hemorrhage, arrhythmias, asthma, 
preeclampsia, Raynaud's disease, percutaneous transluminal coronary 
angioplasty and restenosis, angina, cancer, pulmonary hypertension, 
ischemic disease, gastric mucosal damage, ischemic bowel disease, and 
diabetes. 
Endothelin-1 (ET-1), a potent vasoconstrictor, is a 21 amino acid bicyclic 
peptide that was first isolated from cultured porcine aortic endothelial 
cells. Endothelin-1, is one of a family of structurally similar bicyclic 
peptides which include; ET-2, ET-3, vasoactive intestinal contractor 
(VIC), and the sarafotoxins (SRTX's). The unique bicyclic structure and 
corresponding arrangement of the disulfide bridges of ET-1, which are the 
same for the endothelins, VIC, and the sarafotoxins, has led to 
significant speculation as to the importance of the resulting induced 
secondary structure to receptor binding and functional activity. ET-1 
analogues with incorrect disulfide pairings exhibit at least 100-fold less 
vasoconstrictor activity. The flexible C-terminal hexapeptide of ET-1 has 
been shown to be important for binding to the ET receptor and functional 
activity in selected tissues. Additionally, the C-terminal amino acid 
(Trp-21) has a critical role in binding and vasoconstrictor activity, 
since ET[1-20] exhibits approximately 1000-fold less functional activity. 
Endothelin is involved in many human disease states. 
Several in vivo studies with ET antibodies have been reported in disease 
models. Left coronary artery ligation and reperfusion to induce myocardial 
infarction in the rat heart, caused a four- to sevenfold increase in 
endogenous endothelin levels. Administration of ET antibody was reported 
to reduce the size of the infarction in a dose-dependent manner (Watanabe, 
T., et al, "Endothelin in Myocardial Infarction," i Nature (Lond.) 344:114 
(1990)). Thus, ET may be involved in the pathogenesis of congestive heart 
failure and myocardial ischemia (Margulies, K. B., et al, "Increased 
Endothelin in Experimental Heart Failure," Circulation 82:2226 (1990)). 
Studies by Kon and colleagues using anti-ET antibodies in an ischemic 
kidney model, to deactivate endogenous ET, indicated the peptide's 
involvement in acute renal ischemic injury (Kon, V., et al, "Glomerular 
Actions of Endothelin In Vivo," J. Clin. Invest. 83:1762 (1989)). In 
isolated kidneys, preexposed to specific antiendothelin antibody and then 
challenged with cyclosporine, the renal perfusate flow and glomerular 
filtration rate increased, while renal resistance decreased as compared 
with isolated kidneys preexposed to a nonimmunized rabbit serum. The 
effectiveness and specificity of the anti-ET antibody were confirmed by 
its capacity to prevent renal deterioration caused by a single bolus dose 
(150 pmol) of synthetic ET, but not by infusion of angiotensin II, 
norepinephrine, or the thromboxane A.sub.2 mimetic U-46619 in isolated 
kidneys (Perico, N., et al, "Endothelin Mediates the Renal 
Vasoconstriction Induced by Cyclosporine in the Rat," J. Am. Soc. Nephrol. 
1:76 (1990)). 
Others have reported inhibition of ET-1 or ET-2-induced vasoconstriction in 
rat isolated thoracic aorta using a monoclonal antibody to ET-1 (Koshi, 
T., et al, "Inhibition of Endothelin (ET)-1 and ET-2-Induced 
Vasoconstriction by Anti-ET-1 Monoclonal Antibody," Chem. Pharm. Bull., 
39:1295 (1991)). 
Combined administration of ET-1 and ET-1 antibody to rabbits showed 
significant inhibition of the BP and renal blood flow responses (Miyamori, 
I., et al, "Systemic and Regional Effects of Endothelin in Rabbits: 
Effects of Endothelin Antibody," Clin. Exp. Pharmacol, Physiol., 17:691 
(1990)). 
Other investigators have reported that infusion of ET-specific antibodies 
into spontaneously hypertensive rats (SHR) decreased mean arterial 
pressure (MAP), and increased glomerular filtration rate and renal blood 
flow. In the control study with normotensive Wistar-Kyoto rats (WKY) there 
were no significant changes in these parameters (Ohno, A. "Effects of 
Endothelin-Specific Antibodies and Endothelin in Spontaneously 
Hypertensive Rats," J. Tokyo Women's Med. Coll., 61:951 (1991)). 
In addition, elevated levels of endothelin have been reported in several 
disease states (see Table I below). 
Burnett and co-workers recently demonstrated that exogenous infusion of ET 
(2.5 ng/kg/mL) to anesthetized dogs, producing a doubling of the 
circulating concentration, did have biological actions (Lerman, A., et al, 
"Endothelin has Biological Actions at Pathophysiological Concentrations," 
Circulation 83:1808 (1991)). Thus heart rate and cardiac output decreased 
in association with increased renal and systemic vascular resistances and 
antinatriuresis. These studies support a role for endothelin in the 
regulation of cardiovascular, renal, and endocrine function. 
In the anesthetized dog with congestive heart failure, a significant two- 
to threefold elevation of circulating ET levels has been reported (Cavero, 
P. G., et al, "Endothelin in Experimental Congestive Heart Failure in the 
Anesthetized Dog," Am. J. Physiol. 259:F312 (1990)), and studies in humans 
have shown similar increases (Rodeheffer, R. J., et al, "Circulating 
Plasma Endothelin Correlates With the Severity of Congestive Heart Failure 
in Humans," Am. J. Hypertension 4:9A (1991)). When ET was chronically 
infused into male rats, to determine whether a long-term increase in 
circulating ET levels would cause a sustained elevation in mean arterial 
blood pressure, significant, sustained, and dose-dependent increases in 
mean arterial BP were observed. Similar results were observed with ET-3 
although larger doses were required (Mortenson, L. H., et al, "Chronic 
Hypertension Produced by Infusion of Endothelin in Rats," Hypertension, 
15:729 (1990)). 
The distribution of the two cloned receptor subtypes, termed ET.sub.A and 
ET.sub.B, have been studied extensively (Arai, H., et al, Nature 348:730 
(1990), Sakurai, T., et al, Nature 348:732 (1990)). The ET.sub.A, or 
vascular smooth muscle receptor, is widely distributed in cardiovascular 
tissues and in certain regions of the brain (Lin, H. Y., et al, Proc. 
Natl. Acad. Sci. 88: 3185 (1991)) . The ET.sub.B receptor, originally 
cloned from rat lung, has been found in rat cerebellum and in endothelial 
cells, although it is not known if the ET.sub.B receptors are the same 
from these sources. The human ET receptor subtypes have been cloned and 
expressed (Sakamoto, A., et al, Biochem. Biophys. Res. Chem. 178:656 
(1991), Hosoda, K., et al, FEBS Lett. 287:23 (1991)). The ET.sub.A 
receptor clearly mediates vasoconstriction and there have been a few 
reports implicating the ET.sub.B receptor in the initial vasodilatory 
response to ET (Takayanagi, R., et al, FEBS Lett. 282:103 (1991)) . 
However, recent data has shown that the ET.sub.B receptor can also mediate 
vasoconstriction in some tissue beds (Panek, R. L., et al, Biochem. 
Biophys. Res. Commun. 183(2):566 (1992)). 
Comparison of the receptor affinities of the ET's and SRTX's in rats and 
atria (ET.sub.A) or cerebellum and hippocampus (ET.sub.B), indicate that 
SRTX-c is a selective ET.sub.B ligand (Williams, D. L., et al, Biochem. 
Biophys. Res. Commun., 175:556 (1991)) . A recent study showed that 
selective ET.sub.B agonists caused only vasodilation in the rat aortic 
ring, possibly through the release of EDRF from the endothelium (ibid) . 
Thus, reported selective ET.sub.B agonists, for example, the linear analog 
ET[1,3,11,15-Ala] and truncated analogs ET[6-21, 1,3,11,15-Ala], 
ET[8-21,11,15-Ala], and N-Acetyl-ET [10-21,11,15-Ala] caused 
vasorelaxation in isolated, endothelium-intact porcine pulmonary arteries 
(Saeki, T., et al, Biochem. Biophys. Res. Commun. 179:286 (1991)). 
However, some ET analogs are potent vasoconstrictors in the rabbit 
pulmonary artery, a tissue that appears to possess an ET.sub.B y, 
nonselective type of receptor (ibid). 
Plasma endothelin-1 levels were dramatically increased in a patient with 
malignant hemangioendothelioma (K. Nakagawa et al, Nippon Hifuka Gakkai 
Zasshi, 1990, 100, 1453-1456). 
The ET receptor antagonist BQ-123 has been shown to block ET-1 induced 
bronchoconstriction and tracheal smooth muscle contraction in allergic 
sheep providing evidence for expected efficacy in bronchopulmonary 
diseases such as asthma (Noguchi, et al, Am. Rev. Respir. Dis., 1992, 145 
(4 Part 2), A858). 
Circulating endothelin levels are elevated in women with preeclampsia and 
correlate closely with serum uric acid levels and measures of renal 
dysfunction. These observations indicate a role for ET in renal 
constriction in preeclampsia (Clark B. A., et al, Am. J. Obstet. Gynecol., 
1992, 166, 962-968). 
Plasma immunoreactive endothelin-1 concentrations are elevated in patients 
with sepsis and correlate with the degree of illness and depression of 
cardiac output (Pittett J., et al, Ann Surg., 1991, 213(3), 262) . 
In addition the ET-1 antagonist BQ-123 has been evaluated in a mouse model 
of endotoxic shock. This ET.sub.A antagonist significantly increased the 
survival rate in this model (Toshiaki M., et al, 20.12.90. EP 0 436 189 
A1). 
Endothelin is a potent agonist in the liver eliciting both sustained 
vasoconstriction of the hepatic vasculature and a significant increase in 
hepatic glucose output (Gandhi C. B., et al, Journal of Biological 
Chemistry, 1990, 265(29), 17432). In streptozotocin-diabetic rats there is 
an increased sensitivity to endothelin-1 (Tammesild P. J., et al, Clin. 
Exp. Pharmacol. Physiol., 1992, 19(4), 261). In addition increased levels 
of plasma ET-1 have been observed in microalbuminuric insulin-dependent 
diabetes mellitus patients indicating a role for ET in endocrine disorders 
such as diabetes (Collier A., et al, Diabetes Care, 1992, 15(8), 1038). 
ET.sub.A antagonist receptor blockade has been found to produce an 
antihypertensive effect in normal to low renin models of hypertension with 
a time course similar to the inhibition of ET-1 pressor responses (Basil 
M. K., et al, J. Hypertension, 1992, 10(Suppl 4), S49). The endothelins 
have been shown to be arrhythmogenic, and to have positive chronotropic 
and inotropic effects, thus ET receptor blockade would be expected to be 
useful in arrhythmia and other cardiovascular disorders (Hah S.-P., et al, 
Life Sci., 1990, 46, 767). 
The widespread localization of the endothelins and their receptors in the 
central nervous system and cerebrovascular circulation has been described 
(Nikolov R. K., et al, Drugs of Today, 1992, 28(5), 303-310). 
Intracerebroventricular administration of ET-1 in rats has been shown to 
evoke several behavioral effects. These factors strongly suggest a role 
for the ETs in neurological disorders. The potent vasoconstrictor action 
of ETs on isolated cerebral arterioles suggests the importance of these 
peptides in the regulation of cerebrovascular tone. Increased ET levels 
have been reported in some CNS disorders, i.e., in the CSF of patients 
with subarachnoid hemorrhage and in the plasma of women with preeclampsia. 
Stimulation with ET-3 under conditions of hypoglycemia have been shown to 
accelerate the development of striatal damage as a result of an influx of 
extracellular calcium. Circulating or locally produced ET has been 
suggested to contribute to regulation of brain fluid balance through 
effects on the choroid plexus and CSF production. ET-1 induced lesion 
development in a new model of local ischemia in the brain has been 
described. 
Circulating and tissue endothelin immunoreactivity is increased more than 
twofold in patients with advanced atherosclerosis (A. Lerman, et al, New 
England J. Med., 1991, 325, 997-1001). Increased endothelin 
immunoreactivity has also been associated with Buerger's disease (K. 
Kanno, et al, J. Amer. Med. Assoc., 1990, 264, 2868) and Raynaud's 
phenomenon (M. R. Zamora, et al, Lancet, 1990, 336, 1144-1147). Likewise, 
increased endothelin concentrations were observed in hypercholesterolemic 
rats (T. Horio, et al, Atherosclerosis, 1991, 89, 239-245). 
An increase of circulating endothelin levels was observed in patients that 
underwent percutaneous transluminal coronary angioplasty (PTCA) (A. 
Tahara, et al, Metab. Clin. Exp., 1991, 40, 1235-1237, K. Sanjay, et al, 
Circulation, 1991, 84(Suppl. 4), 726). 
Increased plasma levels of endothelin have been measured in rats (T. J. 
Stelzner, et al, Am. J. Physiol, 1992, 262, L614-L620) and individuals (T. 
Miyauchi, et al, Jpn. J. Pharmacol., 1992, 58, 279P, D. J. Stewart, et al, 
Ann. Internal Medicine, 1991, 114 464-469) with pulmonary hypertension. 
Elevated levels of endothelin have also been measured in patients suffering 
from ischemic heart disease (M. Yasuda, et al, Amer. Heart J., 1990, 119 
801-806, S. G. Ray, et al, Br. Heart J., 1992, 67, 383-386) and either 
stable or unstable angina (J. T. Stewart, et al, Br. Heart J., 1991, 66, 
7-9). 
Infusion of an endothelin antibody 1 h prior to and 1 h after a 60 minute 
period of renal ischaemia resulted in changes in renal function versus 
control. In addition, an increase in glomerular platelet-activating factor 
was attributed to endothelin (A. Lopez-Farre, et al, J. Physiology, 1991, 
444, 513- 522). In patients with chronic renal failure as well as in 
patients on regular hemodialysis treatment mean plasma endothelin levels 
were significantly increased (F. Stockenhuber, et al, Clin. Sci. (Lond.), 
1992, 82, 255-258). In addition it has been suggested that the 
proliferative effect of endothelin on mesangial cells may be a 
contributing factor in chronic renal failure (P. J. Schultz, J. Lab. Clin. 
Med., 1992, 119, 448-449). 
Local intra-arterial administration of endothelin has been shown to induce 
small intestinal mucosal damage in rats in a dose-dependent manner (S. 
Mirua, et al, Digestion, 1991, 48, 163-172). Administration of 
endothelin-1 in the range of 50-500 pmol/kg into the left gastric artery 
increased the tissue type plasminogen activator release and platelet 
activating formation, and induced gastric mucosal haemorrhagic change in a 
dose dependent manner (I. Kurose, et al, Gut, 1992, 33, 868-871). 
Furthermore, it has been shown that an anti-ET-1 antibody reduced 
ethanol-induced vasoconstriction in a concentration-dependent manner (E. 
Masuda, et al, Am. J. Physiol., 1992, 262, G785-G790). Elevated endothelin 
levels have been observed in patients suffering from Crohn's disease and 
ulcerative colitis (S. H. Murch, et al, Lancet, 1992, 339, 381-384). 
TABLE I 
______________________________________ 
Plasma Concentrations of ET-1 in Humans 
ET Plasma 
Normal Levels Reported 
Condition Control (pg/ML) 
______________________________________ 
Atherosclerosis 1.4 3.2 pmol/L 
Surgical operation 
1.5 7.3 
Buerger's disease 
1.6 4.8 
Takayasu's arteritis 
1.6 5.3 
Cardiogenic shock 
0.3 3.7 
Congestive heart 
9.7 20.4 
failure (CHF) 
Mild CHF 7.1 11.1 
Severe CHF 7.1 13.8 
Dilated cardiomyopathy 
1.6 7.1 
Preeclampsia 10.4 pmol/L 22.6 pmol/L 
Pulmonary hypertension 
1.45 3.5 
Acute myocardial 
1.5 3.3 
infarction 
(several reports) 
6.0 11.0 
0.76 4.95 
0.50 3.8 
Subarachnoid hemorrhage 
0.4 2.2 
Crohn's Disease 0-24 fmol/mg 
4-64 fmol/mg 
Ulcerative colitis 
0-24 fmol/mg 
20-50 fmol/mg 
Cold pressor test 
1.2 8.4 
Raynaud's phenomenon 
1.7 5.3 
Raynaud's/hand cooling 
2.8 5.0 
Hemodialysis &lt;7 10.9 
(several reports) 
1.88 4.59 
Chronic renal failure 
1.88 10.1 
Acute renal failure 
1.5 10.4 
Uremia before 0.96 1.49 
hemodialysis 
Uremia after hemodialysis 
0.96 2.19 
Essential hypertension 
18.5 33.9 
Sepsis syndrome 6.1 19.9 
Postoperative cardiac 
6.1 11.9 
Inflammatory arthritides 
1.5 4.2 
Malignant 4.3 16.2 
hemangioendothelioma 
(after 
removal) 
______________________________________ 
Rovero, P., et al, British Journal of Pharmacology 101, pages 232-236 
(1990) disclosed various analogs of the C-terminal hexapeptide of ET-1, 
none of which were reported to be antagonists of ET-1. 
Doherty, A. M., et al, Abstract, Second International Conference on 
Endothelin, Tsukuba, Japan, Dec. 9, 1990, and the published manuscript (J. 
Cardiovasc. Pharm. 17 (Suppl. 7), 1991, pp. 559-561) disclosed various 
analogs of the C-terminal hexapeptide of ET-1, none of which exhibited any 
functional activity. 
However, we have surprisingly and unexpectedly found that a series of 
C-terminal hexapeptide and related analogs of ET-1 are receptor 
antagonists of endothelin. Additional data for the activity of this series 
of peptides is found in the following references (W. L. Cody, et al, J. 
Med. Chem., 1992, 35, 3301-3303., D. M. LaDouceur, et al, FASEB, 1992). 
SUMMARY OF THE INVENTION 
Accordingly, the present invention is a compound of Formula I 
EQU AA.sup.1 -AA.sup.2 -AA.sup.3 -AA.sup.4 -AA.sup.5 -AA.sup.6 
wherein AA.sup.1 is 
##STR1## 
wherein R is 
hydrogen 
alkyl, 
alkenyl, 
alkynyl, 
cycloalkyl, 
cycloalkylalkyl, 
aryl, 
heteroaryl, 
fluorenylmethyl, 
##STR2## 
wherein R.sup.3 and R.sup.4 are each the same or different and each is 
hydrogen, 
alkyl, 
alkenyl, 
alkynyl, 
cycloalkyl, 
cycloalkylalkyl, 
aryl, 
heteroaryl, or 
fluorenylmethyl, 
--OR.sup.3 wherein R.sup.3 is as defined above, 
##STR3## 
wherein R.sup.3 is as defined above 
##STR4## 
wherein R.sup.3 and R.sup.4 are each the same or different and each is as 
defined above, 
##STR5## 
wherein R.sup.3 and R.sup.4 are each the same or different and each is as 
defined above, but R.sup.4 is not hydrogen, 
##STR6## 
wherein R.sup.3 is as defined above, 
##STR7## 
wherein R.sup.3 and R.sup.4 are defined above, 
##STR8## 
wherein R.sup.3' is F, Cl, Br, or I, and R.sup.3 is as defined above, or 
--CH2OR.sup.3 wherein R.sup.3 is as defined above, 
n is zero or an integer of 1, 2, 3, 4, 5, or 6 and 
R.sup.2 is 
hydrogen, 
alkyl, 
trityl, 
##STR9## 
wherein R.sup.3 and R.sup.4 are each the same or different and each is as 
defined above, 
##STR10## 
wherein R.sup.5 is 
hydrogen, 
p-toluenesul fonyl, 
nitro or 
##STR11## 
wherein R.sup.6 is 
alkyl, 
cycloalkyl, 
aryl, or 
heteroaryl, 
##STR12## 
wherein R.sup.6 is as defined above, 
##STR13## 
wherein R.sup.3 and R.sup.4 are each the same or different and each is as 
defined above, 
aryl, 
heteroaryl, or 
heterocycloalkyl, 
##STR14## 
wherein n and n' are each the same or different and each is as defined 
above for n, 
R.sup.2 and R.sup.2' are each the same or different and each is as defined 
above for R.sup.2, and R is as defined above, 
##STR15## 
wherein R.sup.2 R.sup.2' and R.sup.2" are each the same or different and 
each is as defined above for R.sup.2, R, and n are defined as above, 
##STR16## 
wherein n and n' are each the same or different and each is as defined 
above for n, 
R.sup.2, R.sup.2' and R.sup.2" are each the same or different and each is 
as defined above for R.sup.2 and R is as defined above, 
##STR17## 
wherein R is as defined above, 
##STR18## 
wherein R is as defined above, 
##STR19## 
wherein R is as defined above, 
##STR20## 
wherein R.sup.8 is 
hydrogen, or 
alkyl, 
and R is as defined above, 
##STR21## 
wherein R.sup.7 is 
hydrogen, 
alkyl, 
cycloalkyl, 
aryl, or 
heteroaryl, 
R.sup.8 and R.sup.9 are each the same or different and each is as defined 
above for R.sup.8 
##STR22## 
wherein R.sup.7, R.sup.8, and R.sup.9 are as defined above or 
##STR23## 
wherein R.sup.7 and R.sup.7' are each the same or different and each is as 
defined above for R.sup.7, and R is as defined above; 
AA.sup.2, AA.sup.3, AA.sup.4, and AA.sup.5 are each independently absent or 
each independently 
##STR24## 
wherein R.sup.10 is 
hydrogen, 
alkyl, 
aryl, 
cycloalkyl, 
alkenyl, 
alkynyl, 
--OR.sup.3 wherein R.sup.3 is as defined above, 
##STR25## 
wherein R.sup.3 and R.sup.4 are each the same or different and each is as 
defined above, 
##STR26## 
wherein R.sup.3 and R.sup.4 are each the same or different and each is as 
defined above, 
##STR27## 
wherein R.sup.5 is as defined above, wherein m is zero or an integer of 1 
or 2, and R.sup.3 is as defined above where R.sup.3 is not hydrogen, 
##STR28## 
wherein R.sup.3 is as defined above, 
##STR29## 
wherein R.sup.3 is as defined above, R.sup.11 is hydrogen, alkyl, or aryl, 
and n is as defined above, 
##STR30## 
wherein n and n' are each the same or different and each is as defined 
above for n, 
R.sup.10 and R.sup.20' are each the same or different and each is as 
defined above for R.sup.10, and R.sup.11 is as defined above, 
##STR31## 
wherein p is an integer of 1, 2, 3, 4, 5, or 6 and R.sup.11 is as defined 
above, 
##STR32## 
wherein q is zero or an integer of 1, 2, 3, or 4, 
##STR33## 
wherein R.sup.2 and R.sup.2' are each the same or different and each is as 
defined above for R.sup.2, and 
##STR34## 
AA.sup.6 is 
##STR35## 
wherein R.sup.13 is --(CH.sub.2).sub.n --CO.sub.2 H wherein n is as 
defined above, --(CH.sub.2).sub.n --OH wherein n is as defined above, or 
##STR36## 
wherein n, R.sup.3, and R.sup.4 are as defined above, 
##STR37## 
wherein R.sup.14 is hydrogen or --CH.sub.2 --CO.sub.2 H R.sup.12 is 
aryl, 
heteroaryl, or 
heterocycloalkyl, and 
R.sup.11 and n are as defined above, 
##STR38## 
wherein n and n' are each the same or different and each is as defined 
above for n, and R.sup.12 and R.sup.12' are each the same or different and 
each is as defined above for R.sup.12 and R.sup.11 and R.sup.13 are as 
defined above, 
##STR39## 
wherein R.sup.12, R.sup.12' and R.sup.12" are each the same or different 
and each is as defined above for R.sup.12 and R.sup.11, R.sup.13 and n are 
as defined above, 
##STR40## 
wherein n and n' are each the same or different and each is as defined 
above for n, 
R.sup.12, R.sup.12', and R.sup.12" are each the same or different and each 
is as defined above for R.sup.12, and R.sup.11 and R.sup.13 are as defined 
above, 
##STR41## 
wherein R.sup.11 and R.sup.13 are as defined above, 
##STR42## 
wherein R.sup.11 and R.sup.13 are as defined above, 
##STR43## 
wherein R.sup.11 and R.sup.13 are as defined above, 
##STR44## 
wherein R.sup.8 and R.sup.9 are each the same or different and each is as 
defined above for R.sup.8 and R.sup.9, and R.sup.13 is as defined above, 
##STR45## 
wherein R.sup.8 and R.sup.9 are each the same or different and each is as 
defined above for R.sup.8 and R.sup.9, and R.sup.13 is as defined above, 
##STR46## 
wherein R.sup.8, R.sup.11, and R.sup.13 are as defined above, and 
##STR47## 
wherein R.sup.11 and p are as defined above; stereochemistry at 
##STR48## 
in AA.sup.1 is D, stereochemistry at 
##STR49## 
in AA.sup.2, AA.sup.3, AA.sup.4 or AA.sup.5 is D, L, or DL and 
stereochemistry at 
##STR50## 
in AA.sup.6 is L; and with the exclusion of the compounds wherein AA.sup.1 
is 
##STR51## 
wherein 
##STR52## 
is D stereochemistry, or 
##STR53## 
wherein 
##STR54## 
is D stereochemistry, AA.sup.2 is 
##STR55## 
wherein 
##STR56## 
is L stereochemistry, AA.sup.3 is 
##STR57## 
wherein 
##STR58## 
is L stereochemistry, AA.sup.4 and AA.sup.5 are each 
##STR59## 
wherein 
##STR60## 
is L stereochemistry, and AA.sup.6 is 
##STR61## 
wherein 
##STR62## 
is L stereochemistry; or a pharmaceutically acceptable salt thereof. 
Elevated levels of endothelin have been postulated to be involved in a 
number of pathophysiological states including diseases associated with the 
cardiovascular system as well as various metabolic and endocrinological 
disorders. As antagonists of endothelin, the compounds of Formula I are 
useful in the treatment of elevated levels of endothelin, acute and 
chronic renal failure, hypertension, myocardial infarction, metabolic, 
endocrinological and neurological disorders, congestive heart failure, 
endotoxic shock, subarachnoid hemorrhage, arrhythmias, asthma, 
preeclampsia, Raynaud's disease, percutaneous transluminal coronary 
angioplasty and restenosis, angina, cancer, pulmonary hypertension, 
ischemic disease, gastric mucosal damage, ischemic bowel disease, and 
diabetes. 
A still further embodiment of the present invention is a pharmaceutical 
composition for administering an effective amount of a compound of Formula 
I in unit dosage form in the treatment methods mentioned above. 
Finally, the present invention is directed to methods for production of a 
compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION 
In the compounds of Formula I, the term "alkyl" means a straight or 
branched hydrocarbon radical having from 1 to 12 carbon atoms and 
includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, 
sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, 
n-nonyl, n-decyl, undecyl, dodecyl, and the like. 
The term "alkenyl" means a straight or branched unsaturated hydrocarbon 
radical having from 2 to 12 carbon atoms and includes, for example, 
ethenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 
3-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 3-heptenyl, 
1-octenyl, 1-nonenyl, 1-decenyl, 1-undecenyl, 1-dodecenyl, and the like. 
The term "alkynyl" means a straight or branched triple bonded unsaturated 
hydrocarbon radical having from 2 to 12 carbon atoms and includes, for 
example, ethynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 
3-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 3-heptynyl, 1-octynyl, 
2-octynyl, 1-nonynyl, 2-nonynyl, 3-nonynyl, 4-nonynyl, 1-decynyl, 
2-decynyl, 2-undecynyl, 3-undecynyl, 3-dodecynyl, and the like. 
The term "cycloalkyl" means a saturated hydrocarbon ring which contains 
from 3 to 12 carbon atoms, for example, cyclopropyl, cyclobutyl, 
cyclopentyl, cyclohexyl, adamantyl, and the like. 
The term "cycloalkylalkyl" means a saturated hydrocarbon ring attached to 
an alkyl group wherein alkyl is as defined above. The saturated 
hydrocarbon ring contains from 3 to 12 carbon atoms. Examples of such are 
cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, adamantylmethyl 
and the like. 
The terms "alkoxy" and "thioalkoxy" are O-alkyl or S-alkyl as defined above 
for alkyl. 
The term "aryl" means an aromatic radical which is a phenyl group, a benzyl 
group, a naphthyl group, a biphenyl group, a pyrenyl group, an anthracenyl 
group, or a fluorenyl group and the like, unsubstituted or substituted by 
1 to 4 substituents selected from alkyl as defined above, alkoxy as 
defined above, thioalkoxy as defined above, hydroxy, thiol, nitro, 
halogen, amino, 
##STR63## 
wherein alkyl is as defined above, 
##STR64## 
wherein alkyl is as defined above, 
##STR65## 
wherein alkyl is as defined above, or aryl. 
The term "heteroaryl" means a heteroaromatic radical which is 2-or 
3-thienyl, 2- or 3-furanyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 
4-, or 5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 
4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5-1,2,4-triazolyl, 4- or 
5-1,2,3-triazolyl, tetrazolyl, 2-, 3-, or 4-pyridinyl, 3-, 4-, or 
5-pyridazinyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 2-, 3-, 4-, 5-, 6-, 
7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 
4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, or 2-, 
4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 
4-, 5-, 6-, or 7-benzothiazolyl, unsubstituted or substituted by 1 to 2 
substituents selected from alkyl as defined above, aryl as defined above, 
alkoxy as defined above, thioalkoxy as defined above, hydroxy, thiol, 
nitro, halogen, formyl, amino, 
##STR66## 
wherein alkyl is as defined above, 
##STR67## 
wherein alkyl is as defined above, 
##STR68## 
wherein alkyl is as defined above or phenyl. 
The term "heterocycloalkyl" means 2- or 3-tetrahydrothieno, 2- or 
3-tetrahydrofurano, 2- or 3-pyrrolidino, 2-, 4-, or 5-thiazolidino, 2-, 
4-, or 5-oxazolidino, 2-, 3-, or 4-piperidino, N-morpholinyl or 
N-thiamorpholinyl. 
"Halogen" is fluorine, chlorine, bromine or iodine. 
The following table provides a list of abbreviations and definitions 
thereof used in the present invention. 
TABLE 
______________________________________ 
Abbreviation* 
Amino Acid 
______________________________________ 
Ala Alanine 
Arg Arginine 
Asn Asparagine 
Asp Aspartic acid 
Cys Cysteine 
Glu Glutamic acid 
Gln Glutamine 
Gly Glycine 
His Histidine 
Ile Isoleucine 
Leu Leucine 
______________________________________ 
Abbreviation Amino Acid 
______________________________________ 
Lys Lysine 
Met Methionine 
Phe Phenylalanine 
Pro Proline 
Ser Serine 
Thr Threonine 
Trp Tryptophan 
Tyr Tyrosine 
Val Valine 
______________________________________ 
Abbreviation* 
Modified and Unusual Amino Acid 
______________________________________ 
Adm Adamantyl alanine 
Ahp 7-Amino heptanoic acid 
Ana 9-Anthracene alanine 
Apa 5-Amino pentanoic acid 
Bip (Paraphenyl)phenylalanine 
Dip 3,3-Diphenylalanine** 
3Hyp 3-Hydroxyproline 
4Hyp 4-Hydroxyproline 
N-MeAsp N-Methyl-Aspartic acid 
N-MeDip N-Methyl-3,3-Diphenylalanine 
N-MeIle N-Methyl-Isoleucine 
N-MeLeu N-Methyl-Leucine 
N-MePhe N-Methyl-Phenylalanine 
N-MeTrp N-Methyl-Tryptophan 
Nva Norvaline 
Nle Norleucine 
Orn Ornithine 
Abu 2-Aminobutyric acid 
______________________________________ 
Alg 2-Amino-4-pentenoic acid 
(Allylglycine) 
Arg(NO.sub.2) 
N.sup.G -nitroarginine 
Atm 2-Amino-3-(2-amino-5- 
thiazole)propanoic acid 
Cpn 2-Amino-3-cyclopropanepropanoic acid 
(Cyclopropylalanine) 
Chx Cyclohexylalanine (Hexahydrophenyl- 
alanine) 
Dopa 3,4-Dihydroxyphenylalanine 
Emg 2-Amino-4,5(RS)-epoxy-4-pentenoic 
acid 
His(Dnp) N.sup.im -2,4-Dinitrophenylhistidine 
HomoArg Homoarginine 
HomoGlu 2-Aminoadipic acid 
HomoPhe 2-Amino-5-phenylpentanoic acid 
(Homophenylalanine) 
HomoLys 2,7-Diamino-Heptanoic acid 
(Homolysine) 
Met(O) Methionine sulfoxide 
Met(O.sub.2) Methionine sulfone 
1-Nal 3-(1'-Naphthyl)alanine 
2-Nal 3-(2'-Naphthyl)alanine 
Nia 2-Amino-3-cyanopropanoic acid 
(Cyanoalanine) 
Pgl Phenylglycine 
Pgy 2-Aminopentanoic acid (Propylglycine) 
Pha 2-Amino-6-(1-pyrrolo)-hexanoic acid 
Pmp Pentamethylphenylalanine 
Pyr 2-Amino-3-(3-pyridyl)-propanoic acid 
(3-Pyridylalanine) 
Tic 1,2,3,4-Tetrahydro-3- 
isoquinolinecarboxylic acid 
Tza 2-Amino-3-(4-thiazolyl)-propanoic 
acid 
Tyr(Ot-Bu) O-tertiary butyl-tyrosine 
Tyr(OMe) O-Methyl-tyrosine 
Tyr(OEt) O-Ethyl-tyrosine 
Trp(For) N.sup.in -Formyltryptophan 
Trp-NH.sub.2 Tryptophan carboxamide 
______________________________________ 
Abbreviation Protecting Group 
______________________________________ 
Ac Acetyl 
Ada 1-Adamantyl acetic acid 
Adoc Adamantyloxycarbonyl 
Bppa 2,2-Diphenylpropionyl 
Bz Benzylcarbonyl 
Bzl Benzyl 
CF.sub.3 CO Trifluoroacetyl 
Cxl Cyclohexylacetyl 
Cxl(U) Cyclohexylurea 
Et Propionyl 
Pya 3-Pyridylacetyl 
MeBzl 4-Methylbenzyl 
Me(U) Methylurea 
Z Benzyloxycarbonyl 
2-Br-Z ortho-Bromobenzyloxycarbonyl 
2-Cl-Z ortho-Chlorobenzyloxycarbonyl 
Bom Benzyloxymethyl 
Boc tertiary Butyloxycarbonyl 
tBu t-Butylcarbonyl 
TBS tertiary Butyldimethylsilyl 
Dnp 2,4-Dinitrophenyl 
For Formyl 
Fmoc 9-Fluorenylmethyloxycarbonyl 
NO.sub.2 Nitro 
Tos 4-Toluenesulfonyl (tosyl) 
Trt Triphenylmethyl (trityl) 
______________________________________ 
Abbreviation Solvents and Reagents 
______________________________________ 
HOAc Acetic acid 
CH.sub.3 CN Acetonitrile 
DCM Dichloromethane 
DCC N,N'-Dicyclohexylcarbodiimide 
DIEA N,N-Diisopropylethylamine 
DMF Dimethylformamide 
HCl Hydrochloric acid 
HF Hydrofluoric acid 
HOBt 1-Hydroxybenzotriazole 
KOH Potassium hydroxide 
TFA Trifluoroacetic acid 
MBHA Resin Methylbenzhydrylamine resin 
PAM Resin 4-(Oxymethyl)-phenylacetamidomethyl 
resin 
______________________________________ 
*If the optical activity of the amino acid is other than L(S), the amino 
acid or abbreviation is preceded by the appropriate configuration D(R) or 
DL(RS). 
**Synthesis can be accomplished according to the procedure described by 
Josien, H., et al, Tetrahedron Letters, 1991, 32, 6547-50. 
The compounds of Formula I are capable of further forming both 
pharmaceutically acceptable acid addition and/or base salts. All of these 
forms are within the scope of the present invention. 
Pharmaceutically acceptable acid addition salts of the compounds of Formula 
I include salts derived from nontoxic inorganic acids such as 
hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, 
hydrofluoric, phosphorous, and the like, as well as the salts derived from 
nontoxic organic acids, such as aliphatic mono- and dicarboxylic acids, 
phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic 
acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such 
salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, 
nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, 
metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, 
trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, 
succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, 
chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, 
benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, 
maleate, tartrate, methanesulfonate, and the like. Also contemplated are 
salts of amino acids such as arginate and the like and gluconate, 
galacturonate (see, for example, Berge, S. M., et al, "Pharmaceutical 
Salts," Journal of Pharmaceutical Science, 66, pp. 1-19 (1977)). 
The acid addition salts of said basic compounds are prepared by contacting 
the free base form with a sufficient amount of the desired acid to produce 
the salt in the conventional manner. Preferably a peptide of Formula I can 
be converted to an acidic salt by treating with an aqueous solution of the 
desired acid, such that the resulting pH is less than 4. The solution can 
be passed through a C18 cartridge to absorb the peptide, washed with 
copious amounts of water, the peptide eluted with a polar organic solvent 
such as, for example, methanol, acetonitrile, and the like, and isolated 
by concentrating under reduced pressure followed by lyophilization. The 
free base form may be regenerated by contacting the salt form with a base 
and isolating the free base in the conventional manner. The free base 
forms differ from their respective salt forms somewhat in certain physical 
properties such as solubility in polar solvents, but otherwise the salts 
are equivalent to their respective free base for purposes of the present 
invention. 
Pharmaceutically acceptable base addition salts are formed with metals or 
amines, such as alkali and alkaline earth metals or organic amines. 
Examples of metals used as cations are sodium, potassium, magnesium, 
calcium, and the like. Examples of suitable amines are 
N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, 
dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, 
for example, Berge, S. M., et al, "Pharmaceutical Salts," Journal of 
Pharmaceutical Science, 66, pp. 1-19 (1977)). 
The base addition salts of said acidic compounds are prepared by contacting 
the free acid form with a sufficient amount of the desired base to produce 
the salt in the conventional manner. Preferably, a peptide of Formula I 
can be converted to a base salt by treating with an aqueous solution of 
the desired base, such that the resulting pH is greater than 9. The 
solution can be passed through a C18 cartridge to absorb the peptide, 
washed with copious amounts of water, the peptide eluted with a polar 
organic solvent such as, for example, methanol, acetonitrile and the like, 
and isolated by concentrating under reduced pressure followed by 
lyophilization. The free acid form may be regenerated by contacting the 
salt form with an acid and isolating the free acid in the conventional 
manner. The free acid forms differ from their respective salt forms 
somewhat in certain physical properties such as solubility in polar 
solvents, but otherwise the salts are equivalent to their respective free 
acid for purposes of the present invention. 
Certain of the compounds of the present invention can exist in unsolvated 
forms as well as solvated forms, including hydrated forms. In general, the 
solvated forms, including hydrated forms, are equivalent to unsolvated 
forms and are intended to be encompassed within the scope of the present 
invention. 
Certain of the compounds of the present invention possess one or more 
chiral centers and each center may exist in the R(D) or S(L) 
configuration. The present invention includes all enantiomeric and 
epimeric forms as well as the appropriate mixtures thereof. 
A preferred compound of Formula I is one wherein AA.sup.1 is 
##STR69## 
wherein R is 
hydrogen 
alkyl, 
alkenyl, 
alkynyl, 
cycloalkyl, 
cycloalkylalkyl, 
aryl, 
heteroaryl, 
fluorenylmethyl, 
##STR70## 
wherein R.sup.3 and R.sup.4 are each the same or different and each is 
hydrogen, 
alkyl, 
alkenyl, 
alkynyl, 
cycloalkyl, 
cycloalkylalkyl, 
aryl, 
heteroaryl, or 
fluorenylmethyl, 
##STR71## 
wherein R.sup.3 and R.sup.4 are each the same or different and each is as 
defined above or 
##STR72## 
wherein R.sup.3 and R.sup.4 are each the same or different and each is as 
defined above, 
##STR73## 
wherein R.sup.3 and R.sup.4 are defined above, or 
##STR74## 
wherein R.sup.3' is F, Cl, Br, or I, and R.sup.3 is as defined above, n is 
zero, 
R.sup.2 is hydrogen or methyl, 
n' is zero or an integer of 1, 2, or 3, and 
R.sup.2' is 
hydrogen, 
trityl, 
aryl, 
heteroaryl, 
heterocycloalkyl, 
##STR75## 
wherein R.sup.3 and R.sup.4 are each the same or different and each is as 
defined above or 
##STR76## 
wherein R.sup.7 is 
hydrogen, 
alkyl, 
aryl, or 
heteroaryl, 
R.sup.8 and R.sup.9 are each the same or different and each is hydrogen or 
alkyl, 
##STR77## 
wherein R.sup.2", R.sup.2'", and R.sup.2"" are each the same or different 
and each is hydrogen, 
alkyl, 
aryl, or 
heteroaryl with the proviso that at least one of R.sup.2", R.sup.2'", and 
R.sup.2"" is aryl or heteroaryl and R.sup.2, n, and n' are as defined 
above, or 
##STR78## 
wherein R.sup.7 and R.sup.7' are each the same or different and each is 
hydrogen, 
alkyl, 
cycloalkyl, 
aryl, or 
heteroaryl; 
AA.sup.2, AA.sup.3, AA.sup.4, and AA.sup.5 are each independently absent or 
each independently; 
Ahp, 
Dip, 
Apa, 
Pro, 
Phe, or 
##STR79## 
wherein R.sup.11 is 
hydrogen or methyl, 
n is zero, 
R.sup.10' is hydrogen or methyl, 
n' is zero or an integer of 1, 2, 3, or 4 and 
R.sup.10' is 
hydrogen, 
alkyl, 
cycloalkyl, 
alkenyl, 
alkynyl, 
--OR.sup.3" wherein R.sup.3" is 
hydrogen, 
alkyl, 
alkenyl, 
cycloalkyl, 
aryl, or 
heteroaryl, 
##STR80## 
wherein R.sup.3" and R.sup.4' are each the same or different and each is 
as defined above for R.sup.3", 
##STR81## 
wherein R.sup.3" and R.sup.4' are each the same or different and each is 
as defined above for R.sup.3", 
##STR82## 
wherein R.sup.3" is as defined above, 
##STR83## 
wherein R.sup.5 is defined as above, 
##STR84## 
wherein R.sup.3" is as defined above, --S(O).sub.m R.sup.3" wherein m is 
zero or an integer of 1 or 2 and R.sup.3" is as defined above except that 
R.sup.3" is not hydrogen, or 
##STR85## 
wherein R.sup.4' is as defined above AA.sup.6 is 
##STR86## 
wherein R.sup.11 is hydrogen or methyl, 
n is zero, 
R.sup.12 is hydrogen, or methyl, 
n' is zero or an integer of 1, 2, or 3, 
R.sup.12' is aryl or heteroaryl, 
R.sup.13 is --(CH.sub.2).sub.n --CO.sub.2 H wherein n is as defined above, 
--(CH.sub.2).sub.n --OH wherein n is as defined above, or 
##STR87## 
wherein n, R.sup.3, and R.sup.4 are defined above, 
##STR88## 
wherein R.sup.14 is hydrogen or --CH.sub.2 --CO.sub.2 H, or 
##STR89## 
wherein R.sup.8 and R.sup.9 are each the same or different and each is as 
defined above for and R.sup.9 and R.sup.13 is as defined above, and 
R.sup.8' is hydrogen, formyl, acetyl, Z, Boc, Bzl, or alkyl; 
stereochemistry at C in AA.sup.1 is D, 
stereochemistry at C in AA.sup.2, AA.sup.3, AA.sup.4, or AA.sup.5 is D, L, 
or DL, and stereochemistry at C in AA.sup.6 is L. 
Most preferred compounds of Formula I are one wherein AA.sup.2 is 
##STR90## 
wherein R is 
hydrogen, 
alkyl, 
alkenyl, 
alkynyl, 
cycloalkyl, 
cycloalkylalkyl, 
aryl, 
heteroaryl, 
fluorenylmethyl, 
##STR91## 
wherein R.sup.3 and R.sup.4 are each the same or different and each is 
hydrogen, 
alkyl, 
alkenyl, 
alkynyl, 
cycloalkyl, 
cycloalkylalkyl, 
aryl, 
heteroaryl, or 
fluorenylmethyl, 
##STR92## 
wherein R.sup.3 and R.sup.4 are each the same or different and each is as 
defined above, 
##STR93## 
wherein R.sup.3 and R.sup.4 are each the same or different and each is as 
defined above, and R.sup.2', R.sup.2", and R.sup.2'" are each the same or 
different and each is 
hydrogen, 
alkyl, 
aryl, or 
heteroaryl with the proviso that at least one of R.sup.2, R.sup.2' and 
R.sup.2" is aryl or heteroaryl, and R.sup.2'" is hydrogen or methyl, 
##STR94## 
wherein R.sup.3 and R.sup.4 are defined above, or 
##STR95## 
wherein R.sup.3' is F, C1, Br, or I, and R.sup.3 is as defined above, 
R.sup.2 is hydrogen or methyl, 
n is zero, and 
n' is zero or an integer of 1, 2, or 3, or 
AA.sup.2 is 
Apa, 
Ahp, 
Dip, 
D-Phe, 
Phe, 
HomoArg, 
Arg, or 
##STR96## 
wherein R.sup.11 is hydrogen or methyl, 
n is zero, 
R.sup.10 is hydrogen or methyl, 
n' is zero or an integer of 1, 2, 3, 4, or 5, and 
R.sup.10 ' is alkyl, 
##STR97## 
wherein R.sup.3" and R.sup.4' are each the same or different and each is 
hydrogen, 
alkyl, or 
aryl, 
##STR98## 
wherein R.sup.3" and R.sup.4' are as defined above, 
##STR99## 
wherein R.sup.4' is as defined above; --S(O).sub.m R.sup.3" wherein m is 
zero or an integer of 1 of 2 and R.sup.3" is as defined above except that 
R.sup.3" is not hydrogen; 
AA.sup.3 is 
Lys, 
Tyr, 
Phe, or 
##STR100## 
wherein R.sup.11 is hydrogen or methyl, 
n is zero, 
R.sup.10 is hydrogen or methyl, 
n" is zero or an integer of 1, 2, or 3, and 
R.sup.10' is 
alkyl, 
aryl, 
##STR101## 
wherein R.sup.3" and R.sup.4' are as defined above, 
##STR102## 
wherein R.sup.4' is as defined above, AA.sup.4 and AA.sup.5 are each 
Phe, 
Lys, 
Glu, 
Pro, or 
##STR103## 
wherein R.sup.11 is hydrogen or methyl, 
n is zero, 
R.sup.10 is hydrogen or methyl, 
n' is zero, and 
R.sup.10' is alkyl, or cycloalkyl, 
AA.sup.6 is 
##STR104## 
wherein R.sup.11 is hydrogen or methyl, 
n is zero, 
R.sup.12 is hydrogen, or methyl, 
n' is zero or an integer of 1, 2, of 3, 
R.sup.12' is aryl or heteroaryl, 
R.sup.13 is 
--(CH.sub.2).sub.n --CO.sub.2 .sup.H wherein n is zero or an integer of 1, 
2, 3, 4, 5, or 6, 
--(CH.sub.2).sub.n --OH wherein n is zero or an integer of 1, 2, 3, 4, 5, 
or 6, or 
##STR105## 
wherein n, R.sup.3, and R.sup.4 are defined above 
##STR106## 
wherein R.sup.14 is hydrogen or --CH.sub.2 CO.sub.2 H, stereochemistry at 
C in AA.sup.1 is D, 
stereochemistry at C in AA.sup.2, AA.sup.3, AA.sup.4, or AA.sup.5 is D or L 
and 
stereochemistry at C in AA.sup.6 is L. 
A more preferred compound of Formula I is one wherein 
AA.sup.1 is 
D-Adm, 
D-Ana, 
D-Chx, 
D-Dip, 
D-Dopa, 
D-Bip, 
D-His, 
D-His(Dnp), 
D-2-Nal, 
D-1-Nal, 
D-Phe, 
D-Pmp, 
D-Pgl, 
D-Tyr, 
D-Tyr(OMe), 
D-Tyr(OEt), 
D-Tyr(OtBu), 
D-Trp, 
D-Trp(For), 
D-Tic, 
D-Tza, 
D-Pyr, 
Ac-D-Adm, 
Ac-D-Ana, 
Ac-D-Chx, 
Ac-D-Dip, 
Ac-D-Dopa, 
Ac-D-Bip, 
Ac-D-His, 
Ac-D-His(Dnp), 
Ac-D-2-Nal, 
Ac-D-1-Nal, 
Ac-D-N-MeDip, 
Ac-D-Phe, 
Ac-D-Pgl, 
Ac-D-Pmp 
Ac-D-Tyr 
Ac-D-Tyr(OMe), 
Ac-D-Tyr(OEt), 
Ac-D-Tyr(OtBu), 
Ac-D-Trp 
Ac-D-Trp(For), 
Ac-D-Tic, 
Ac-D-Tza, 
Ac-D-Pyr, 
Ada-D-Adm, 
Ada-D-Ana, 
Ada-D-Chx, 
Ada-D-Dip, 
Ada-D-Dopa, 
Ada-D-Bip, 
Ada-D-His, 
Ada-D-His(Dnp), 
Ada-D-2-Nal, 
Ada-D-1-Nal, 
Ada-D-Pmp, 
Ada-D-Phe, 
Ada-D-Pgl, 
Ada-D-Tyr, 
Ada-D-Tyr(OMe), 
Ada-D-Tyr(OEt), 
Ada-D-Tyr(OtBu), 
Ada-D-Trp, 
Ada-D-Trp(For), 
Ada-D-Tic, 
Ada-D-Tza, 
Ada-D-Pyr, 
Adoc-D-Adm, 
Adoc-D-Ana, 
Adoc-D-Chx, 
Adoc-D-Dip, 
Adoc-D-Dopa, 
Adoc-D-Bip, 
Adoc-D-His, 
Adoc-D-His(Dnp), 
Adoc-D-2-Nal, 
Adoc-D-1-Nal, 
Adoc-D-Phe, 
Adoc-D-Pmp, 
Adoc-D-Pgl, 
Adoc-D-Tyr, 
Adoc-D-Tyr(OMe), 
Adoc-D-Tyr(OEt), 
Adoc-D-Tyr(OtBu), 
Adoc-D-Trp, 
Adoc-D-Trp(For), 
Adoc-D-Tic, 
Adoc-D-Tza, 
Adoc-D-Pyr, 
Boc-D-Adm, 
Boc-D-Ana, 
Boc-D-Chx, 
Boc-D-Dip, 
Boc-D-Dopa, 
Boc-D-Bip, 
Boc-D-His, 
Boc-D-His(Dnp), 
Boc-D-2-Nal, 
Boc-D-1-Nal, 
Boc-D-Phe, 
Boc-D-Pmp, 
Boc-D-Pgl, 
Boc-D-Tyr, 
Boc-D-Tyr(OMe), 
Boc-D-Tyr(OEt), 
Boc-D-Tyr(OtBu), 
Boc-D-Trp, 
Boc-D-Trp(For), 
Boc-D-Tic, 
Boc-D-Tza, 
Boc-D-Pyr, 
Z-D-Adm, 
Z-D-Ana, 
Z-D-Chx, 
Z-D-Dip, 
Z-D-Dopa, 
Z-D-Bip, 
Z-D-His, 
Z-D-His(Dnp), 
Z-D-2-Nal, 
Z-D-1-Nal, 
Z-D-Phe, 
Z-D-Pmp, 
Z-D-Pgl, 
Z-D-Tyr, 
Z-D-Tyr(OMe), 
Z-D-Tyr(OEt), 
Z-D-Tyr(OtBu), 
Z-D-Trp, 
Z-D-Trp(For), 
Z-D-Tic, 
Z-D-Tza, 
Z-D-Pyr, 
Fmoc-D-Adm, 
Fmoc-D-Ana, 
Fmoc-D-Chx, 
Fmoc-D-Dip, 
Fmox-D-Dopa, 
Fmoc-D-Bip, 
Fmoc-D-His, 
Fmoc-D-His(Dnp), 
Fmoc-D-2-Nal, 
Fmoc-D-1-Nal, 
Fmoc-D-Phe, 
Fmoc-D-Pmp, 
Fmoc-D-Pgl, 
Fmoc-D-Tyr, 
Fmoc-D-Tyr(OMe), 
Fmoc-D-Tyr(OEt), 
Fmoc-D-Tyr(OtBu), 
Fmoc-D-Trp, 
Fmoc-D-Trp(For), 
Fmoc -D-Tic, 
Fmoc-D-Tza, 
Fmoc-D-Pyr, 
Et-D-Dip, 
Bz-D-Dip, 
Pya-D-Dip, 
Cxl-D-Dip, 
Ada-D-Dip, 
Cxl(U)-D-Dip, 
Me(U)-D-Dip, 
tBu-D-Dip, or 
CF.sub.3 CO-D-Dip; 
AA.sup.2 is 
Ala, 
Alg, 
Ahp, 
Apa, 
Arg, 
Ash, 
Asp, 
Dab, 
D-Dip, 
Glu, 
Gln, 
Gly, 
HomoArg, 
HomoGlu, 
HomoLys, 
Ile, 
Leu, 
D-Leu, 
Lys, 
N-MeLeu, 
Met, 
Met(O), 
Met(O.sub.2), 
Nva, 
Nle, 
Orn, 
Phe, 
D-Phe, 
Tyr, 
Val, or 
AA.sup.2 is absent; 
AA.sup.3 is 
Asn, 
Asp, 
D-Asp, 
N-MeAsp, 
Glu, 
Gln, 
Lys, 
HomoPhe, 
Phe, 
Tyr, or 
AA.sup.3 is absent; 
AA.sup.4 is 
Ala, 
Chx, 
Gly, 
Glu, 
Ile, 
D-Ile, 
Leu, 
Lys, 
Nle, 
N-MeIle, 
Nva, 
Phe, 
Pro, 
Val, or 
AA.sup.4 is absent; 
AA.sup.5 is 
Ala, 
Chx, 
Gly, 
Ile, 
D-Ile, 
Leu, 
Lys, 
Nle, 
N-MeIle, 
Nva, 
Phe, 
Val, or 
AA.sup.5 is absent; and 
AA.sup.6 is 
2-Nal, 
1-Nal, 
N-MeTrp, 
Phe, 
Pyr, 
Trp, 
Trp-NH.sub.2, 
Tyr(OMe), 
Tyr(OEt), 
Tyr(Ot-Bu), 
Tyr, 
Trp-Gly, 
Trp-Asp, 
Trp(For), 
Dip, 
Phe, or 
##STR107## 
Particularly valuable are: D-Phe-Leu-Asp-Ile-Ile-Trp; 
D-His(Dnp)-Leu-Asp-Ile-Ile-Trp; 
D-Trp-Leu-Asp-Ile-Ile-Trp; 
D-Tyr-Leu-Asp-Ile-Ile-Trp; 
D-Tyr(OMe)-Leu-Asp-Ile-Ile-Trp; 
D-Tyr(OEt)-Leu-Asp-Ile-Ile-Trp; 
D-2-Nal-Leu-Asp-Ile-Ile-Trp; 
D-1-Nal-Leu-Asp-Ile-Ile-Trp; 
D-Pgl-Leu-Asp-Ile-Ile-Trp; 
D-Pyr-Leu-Asp-Ile-Ile-Trp; 
D-Tic-Leu-Asp-Ile-Ile-Trp; 
D-Dip-Leu-Asp-Ile-Ile-Trp; 
D-Bip-Leu-Asp-Ile-Ile-Trp; 
Ac-D-Phe-Leu-Asp-Ile-Ile-Trp; 
Ac-D-His (Drip)-Leu-Asp-Ile-Ile-Trp; 
Ac-D-Trp-Leu-Asp-Ile-Ile-Trp; 
Ac-D-Tyr-Leu-Asp-Ile-Ile-Trp; 
Ac-D-Tyr(OMe)-Leu-Asp-Ile-Ile-Trp; 
Ac-D-Tyr(OEt)-Leu-Asp-Ile-Ile-Trp; 
Ac-D-2-Nal-Leu-Asp-Ile-Ile-Trp; 
Ac-D-1-Nal-Leu-Asp-Ile-Ile-Trp; 
Ac-D-Pgl-Leu-Asp-Ile-Ile-Trp; 
Ac-D-Pyr-Leu-Asp-Ile-Ile-Trp; 
Ac-D-Tic-Leu-Asp-Ile-Ile-Trp; 
Ac-D-Dip-Leu-Asp- Ile-Ile-Trp; 
Ac-D-Bip-Leu -Asp-Ile-Ile-Trp; 
Fmoc-D-Phe-Leu-Asp-Ile-Ile-Trp; 
Fmoc-D-His-Leu-Asp-Ile-Ile-Trp; 
Fmoc-D-Trp-Leu-Asp-Ile-Ile-Trp; 
Fmoc-D-Tyr-Leu-Asp-Ile-Ile-Trp; 
Fmoc -D-Tyr(OMe)-Leu-Asp-Ile-Ile-Trp; 
Fmoc-D-Tyr(OEt)-Leu-Asp-Ile-Ile-Trp; 
Fmoc-D-2-Nal-Leu-Asp-Ile-Ile-Trp; 
Fmoc-D-1-Nal-Leu-Asp-Ile-Ile-Trp; 
Fmoc-D-Dip-Leu-Asp-Ile-Ile-Trp; 
Fmoc-D-Bip-Leu-Asp-Ile-Ile-Trp; 
Ada-D-Phe-Leu-Asp-Ile-Ile-Trp; 
Ada-D-His-Leu-Asp-Ile-Ile-Trp; 
Ada-D-Trp-Leu-Asp-Ile-Ile-Trp; 
Ada-D-Tyr-Leu-Asp-Ile-Ile-Trp; 
Ada-D-Tyr(OMe)-Leu-Asp-Ile-Ile-Trp; 
Ada-D-Tyr(OEt)-Leu-Asp-Ile-Ile-TrP; 
Ada-D-2-Nal-Leu-Asp-Ile-Ile-TrP; 
Ada-D-1-Nal-Leu-Asp-Ile-Ile-TrP; 
Ada-D-Dip-Leu-Asp-Ile-Ile-Trp; 
Ada-D-Bip-Leu-Asp-Ile-Ile-Trp; 
Ac-D-Phe-D-Leu-Asp-Ile-Ile-TrP; 
Ac-D-His-D-Leu-Asp-Ile-Ile-TrP; 
Ac-D-Trp-D-Leu-Asp-Ile-Ile-TrP; 
Ac-D-Tyr-D-Leu-Asp-Ile-Ile-TrP; 
Ac-D-Tyr(OMe)-D-Leu-Asp-Ile-Ile-TrP; 
Ac-D-Tyr(OEt)-D-Leu-Asp-Ile-Ile-TrP; 
Ac-D-2-Nal-D-Leu-Asp-Ile-Ile-TrP; 
Ac-D-1-Nal-D-Leu-Asp-Ile-Ile-TrP; 
Ac-D-Dip-D-Leu-Asp-Ile-Ile-TrP; 
Ac-D-Bip-D-Leu-Asp-Ile-Ile-TrP; 
Ac-D-Phe-Ile-Asp-Ile-Ile-Trp; 
Ac-D-His-Ile-Asp-Ile-Ile-TrP; 
Ac-D-Trp-Ile-Asp-Ile-Ile-Trp; 
Ac-D-Tyr-Ile-Asp-Ile-Ile-TrP; 
Ac-D-Tyr(OMe)-Ile-Asp-Ile-Ile-TrP; 
Ac-D-Tyr(OEt)-Ile-Asp-Ile-Ile-TrP; 
Ac-D-2-Nal-Ile-Asp-Ile-Ile-TrP; 
Ac-D-1-Nal-Ile-Asp-Ile-Ile-TrP; 
Ac-D-Dip-Ile-Asp-Ile-Ile-Trp; 
Ac-D-Bip-Ile-Asp-Ile-Ile-Trp; 
Ac-D-Phe-Val-Asp-Ile-Ile-Trp; 
Ac-D-His-Val-Asp-Ile-Ile-Trp; 
Ac-D-Trp-Val-Asp-Ile-Ile-Trp; 
Ac-D-Tyr-Val-Asp-Ile-Ile-Trp; 
Ac-D-Tyr(OMe)-Val-Asp-Ile-Ile-TrP; 
Ac-D-Tyr(OEt)-Val-Asp-Ile-Ile-TrP; 
Ac-D-2-Nal-Val-Asp-Ile-Ile-TrP; 
Ac-D-1-Nal-Val-Asp-Ile-Ile-Trp; 
Ac-D- Dip-Val-Asp-Ile-Ile-Trp; 
Ac-D-Bip-Val-Asp-Ile-Ile-Trp; 
Ac-D-Phe-Dab-Asp-Ile-Ile-Trp; 
Ac-D-His-Dab-Asp-Ile-Ile-Trp; 
Ac-D-Trp-Dab-Asp-Ile-Ile-Trp; 
Ac-D-Tyr(OMe)-Dab-Asp-Ile-Ile-Trp; 
Ac-D-Tyr(OEt)-Dab-Asp-Ile-Ile-Trp; 
Ac-D-2-Nal-Dab-Asp-Ile-Ile-Trp; 
Ac-D-1-Nal-Dab-Asp-Ile-Ile-Trp; 
Ac-D-Dip-Dab-Asp-Ile-Ile-Trp; 
Ac-D-Bip-Dab-Asp-Ile-Ile-Trp; 
Ac-D-Phe-Arg-Asp-Ile-Ile-Trp; 
Ac-D-His-Arg-Asp-Ile-Ile-Trp; 
Ac-D-Trp-Arg-Asp-Ile-Ile-Trp; 
Ac-D-Tyr(OMe)-Arg-Asp-Ile-Ile-Trp; 
Ac-D-Tyr(OEt)-Arg-Asp-Ile-Ile-Trp; 
Ac-D-2-Nal-Arg-Asp-Ile-Ile-Trp; 
Ac-D-1-Nal-Arg-Asp-Ile-Ile-Trp; 
Ac-D-Dip-Arg-Asp-Ile-Ile-Trp; 
Ac-D-Bip-Arg-Asp-Ile-Ile-Trp; 
Ac-D-Phe-HomoLys-Asp-Ile-Ile-Trp; 
Ac-D-His-HomoLys-Asp-Ile-Ile-Trp; 
Ac-D-Trp-HomoLys-Asp-Ile-Ile-Trp; 
Ac-D-Tyr(OMe)-HomoLys-Asp-Ile-Ile-Trp; 
Ac-D-Tyr(OEt)-HomoLys-Asp-Ile-Ile-Trp; 
Ac-D-2-Nal-HomoLys-Asp-Ile-Ile-Trp; 
Ac-D-1-Nal-HomoLys-Asp-Ile-Ile-Trp; 
Ac-D-Dip-HomoLys-Asp-Ile-Ile-Trp; 
Ac-D-Bip-HomoLys-Asp-Ile-Ile-Trp; 
Ac-D-His-Glu-Asp-Ile-Ile-Trp; 
Ac-D-Trp-Glu-Asp-Ile-Ile-Trp; 
Ac-D-Tyr(OMe)-Glu-Asp-Ile-Ile-Trp; 
Ac-D-Tyr(OEt)-Glu-Asp-Ile-Ile-Trp; 
Ac-D-2-Nal-Glu-Asp-Ile-Ile-Trp; 
Ac-D-1-Nal-Glu-Asp-Ile-Ile-Trp; 
Ac-D-Dip-Glu-Asp-Ile-Ile-Trp; 
Ac-D-Bip-Glu-Asp-Ile-Ile-Trp; 
Ac-D-Phe-HomoGlu-Asp-Ile-Ile-Trp; 
Ac-D-His-HomoGlu-Asp-Ile-Ile-Trp; 
Ac-D-Trp-HomoGlu-Asp-Ile-Ile-Trp; 
Ac-D-Tyr(0Me)-HomoGlu-Asp-Ile-Ile-Trp; 
Ac-D-Tyr(0Et)-HomoGlu-Asp-Ile-Ile-Trp; 
Ac-D-2-Nal-HomoGlu-Asp-Ile-Ile-Trp; 
Ac-D-1-Nal-HomoGlu-Asp-Ile-Ile-Trp; 
Ac-D-Dip-HomoGlu-Asp-Ile-Ile-Trp; 
Ac-D-Bip-HomoGlu-Asp-Ile-Ile-Trp; 
Ac-D-Phe-Asp-Asp-Ile-Ile-Trp; 
Ac-D-His-Asp-Asp-Ile-Ile-Trp; 
Ac-D-Trp-Asp-Asp-Ile-Ile-Trp; 
Ac-D-Tyr(OMe)-Asp-Asp-Ile-Ile-Trp; 
Ac-D-Tyr(OEt)-Asp-Asp-Ile-Ile-Trp; 
Ac-D-2-Nal-Asp-Asp-Ile-Ile-Trp; 
Ac-D-1-Nal-Asp-Asp-Ile-Ile-Trp; 
Ac-D-Dip-Asp-Asp-Ile-Ile-Trp; 
Ac-D-Bip-Asp-Asp-Ile-Ile-Trp; 
Ac-D-Phe-Lys-Asp-Ile-Ile-Trp; 
Ac-D-His-Lys-Asp-Ile-Ile-Trp; 
Ac-D-Trp-Lys-Asp-Ile-Ile-Trp; 
Ac-D-Tyr-Lys-Asp-Ile-Ile-Trp; 
Ac-D-Tyr(OMe)-Lys-Asp-Ile-Ile-Trp; 
Ac-D-Tyr(OEt)-Lys-Asp-Ile-Ile-Trp; 
Ac-D-2-Nal-Lys-Asp-Ile-Ile-Trp; 
Ac-D-1-Nal-Lys-Asp-Ile-Ile-Trp; 
Ac-D-Dip-Lys-Asp-Ile-Ile-Trp; 
Ac-D-Bip-Lys-Asp-Ile-Ile-Trp; 
Ac-D-Phe-Orn-Asp-Ile-Ile-Trp; 
Ac-D-His-Orn-Asp-Ile-Ile-Trp; 
Ac-D-Trp-Orn-Asp-Ile-Ile-Trp; 
Ac-D-Tyr-Orn-Asp-Ile-Ile-Trp; 
Ac-D-Tyr(OMe)-Orn-Asp-Ile-Ile-Trp; 
Ac-D-Tyr(OEt)-Orn-Asp-Ile-Ile-Trp; 
Ac-D-2-Nal-Orn-Asp-Ile-Ile-Trp; 
Ac-D-1-Nal-Orn-Asp-Ile-Ile-Trp; 
Ac-D-Dip-Orn-Asp-Ile-Ile-Trp; 
Ac-D-Bip-Orn-Asp-Ile-Ile-Trp; 
Ac-D-Phe-Gln-Asp-Ile-Ile-Trp; 
Ac-D-His-Gln-Asp-Ile-Ile-Trp; 
Ac-D-Trp-Gln-Asp-Ile-Ile-Trp; 
Ac-D-Tyr-Gln-Asp-Ile-Ile-Trp; 
Ac-D-Tyr(OMe)-Gln-Asp-Ile-Ile-TrP; 
Ac-D-Tyr(OEt)-Gln-Asp-Ile-Ile-TrP; 
Ac-D-2-Nal-Gln-Asp-Ile-Ile-TrP; 
Ac-D-1-Nal-Gln-Asp-Ile-Ile-TrP; 
Ac-D-Dip-Gln-Asp-Ile-Ile-Trp; 
Ac-D-Bip-Gln-Asp-Ile-Ile-Trp; 
Ac-D-Phe-Leu-Glu-Ile-Ile-Trp; 
Ac-D-His-Leu-Glu-Ile-Ile-TrP; 
Ac-D-Trp-Leu-Glu-Ile-Ile-Trp; 
Ac-D-Tyr-Leu-Glu-Ile-Ile-Trp; 
Ac-D-Tyr(OMe)-Leu-Glu-Ile-Ile-TrP; 
Ac-D-Tyr(OEt)-Leu-Glu-Ile-Ile-TrP; 
Ac-D-2-Nal-Leu-Glu-Ile-Ile-Trp; 
Ac-D-1-Nal-Leu-Glu-Ile-Ile-TrP; 
Ac-D-Dip-Leu-Glu-Ile-Ile-Trp; 
Ac-D-Bip-Leu-Glu-Ile-Ile-Trp; 
Ac-D-Phe-Leu-Asn-Ile-Ile-Trp; 
Ac-D-His-Leu-Asn-Ile-Ile-Trp; 
Ac-D-Trp-Leu-Asn-Ile-Ile-Trp; 
Ac-D-Tyr-Leu-Asn-Ile-Ile-Trp; 
Ac-D-Tyr(OMe)-Leu-Asn-Ile-Ile-Trp; 
Ac-D-Tyr(OEt)-Leu-Asn-Ile-Ile-Trp; 
Ac-D-2-Nal-Leu-Asn-Ile-Ile-TrP; 
Ac-D-1-Nal-Leu-Asn-Ile-Ile-Trp; 
Ac-D-Dip-Leu-Asn-Ile-Ile-Trp; 
Ac-D-Bip-Leu-Asn-Ile-Ile-Trp; 
Ac-D-Phe-Leu-Phe-Ile-Ile-Trp; 
Ac-D-His-Leu-Phe-Ile-Ile-Trp; 
Ac-D-Trp-Leu-Phe-Ile-Ile-Trp; 
Ac-D-Tyr(OMe)-Leu-Phe-Ile-Ile-TrP; 
Ac-D-Tyr(OEt)-Leu-Phe-Ile-Ile-Trp; 
Ac-D-2-Nal-Leu-Phe-Ile-Ile-Trp; 
Ac-D-1-Nal-Leu-Phe-Ile-Ile-Trp; 
Ac-D-Dip-Leu-Phe-Ile-Ile-Trp; 
Ac-D-Bip-Leu-Phe-Ile-Ile-Trp; 
Ac-D-Phe-Glu-Asp-Ile-Ile-Trp; 
Ac-D-Phe-Leu-Asp-Val-Ile-Trp; 
Ac-D-His-Leu-Asp-Val-Ile-Trp; 
Ac-D-Trp-Leu-Asp-Val-Ile-Trp; 
Ac-D-Tyr-Leu-Asp-Val-Ile-Trp; 
Ac-D-Tyr(OMe)-Leu-Asp-Val-Ile-Trp; 
Ac-D-Tyr(OEt)-Leu-Asp-Val-Ile-Trp; 
Ac-D-2-Nal-Leu-Asp-Val-Ile-Trp; 
Ac-D-1-Nal-Leu-Asp-Val-Ile-Trp; 
Ac-D-Dip-Leu-Asp-Val-Ile-Trp; 
Ac-D-Bip-Leu-Asp-Val-Ile-Trp; 
Ac-D-Phe-Leu-Asp-Chx-Ile-Trp; 
Ac-D-His-Leu-Asp-Chx-Ile-Trp; 
Ac-D-Trp-Leu-Asp-Chx-Ile-Trp; 
Ac-D-Tyr-Leu-Asp-Chx-Ile-Trp; 
Ac-D-Tyr(OMe)-Leu-Asp-Chx-Ile-Trp; 
Ac-D-Tyr(OEt)-Leu-Asp-Chx-Ile-Trp; 
Ac-D-2-Nal-Leu-Asp-Chx-Ile-Trp; 
Ac-D-1-Nal-Leu-Asp-Chx-Ile-Trp; 
Ac-D-Dip-Leu-Asp-Chx-Ile-Trp; 
Ac-D-Bip-Leu-Asp-Chx-Ile-Trp; 
Ac-D-Phe-Leu-Asp-D-Ile-Ile-Trp; 
Ac-D-His-Leu-Asp-D-Ile-Ile-Trp; 
Ac-D-Trp-Leu-Asp-D-Ile-Ile-Trp; 
Ac-D-Tyr-Leu-Asp-D-Ile-Ile-Trp; 
Ac-D-Tyr(OMe)-Leu-Asp-D-Ile-Ile-Trp; 
Ac-D-Tyr(OEt)-Leu-Asp-D-Ile-Ile-Trp; 
Ac-D-2-Nal-Leu-Asp-D-Ile-Ile-Trp; 
Ac-D-1-Nal-Leu-Asp-D-Ile-Ile-Trp; 
Ac-Dip-Leu-Asp-D-Ile-Ile-Trp; 
Ac-Bip-Leu-Asp-D-Ile-Ile-Trp; 
Ac-Phe-Leu-Asp-Ile-D-Ile-Trp; 
Ac-His-Leu-Asp-Ile-D-Ile-Trp; 
Ac-D-Trp-Leu-Asp-Ile-D-Ile-Trp; 
Ac-D-Tyr-Leu-Asp-Ile-D-Ile-Trp; 
Ac-D-Tyr(OMe)-Leu-Asp-Ile-D-Ile-Trp; 
Ac-D-Tyr(OEt)-Leu-Asp-Ile-D-Ile-Trp; 
Ac-D-2-Nal-Leu-Asp-Ile-D-Ile-Trp; 
Ac-D-1-Nal-Leu-Asp-Ile-D-Ile-Trp; 
Ac-D-Dip-Leu-Asp-Ile-D-Ile-Trp; 
Ac-D-Bip-Leu-Asp-Ile-D-Ile-Trp; 
Ac-D-Phe-Leu-Asp-Ile-Val-Trp; 
Ac-D-His-Leu-Asp-Ile-Val-Trp; 
Ac-D-Trp-Leu-Asp-Ile-Val-Trp; 
Ac-D-Tyr-Leu-Asp-Ile-Val-Trp; 
Ac-D-Tyr(OMe)-Leu-Asp-Ile-Val-Trp; 
Ac-D-Tyr(OEt)-Leu-Asp-Ile-Val-Trp; 
Ac-D-2-Nal-Leu-Asp-Ile-Val-Trp; 
Ac-D-1-Nal-Leu-Asp-Ile-Val-Trp; 
Ac-D-Dip-Leu-Asp-Ile-Val-Trp; 
Ac-D-Bip-Leu-Asp-Ile-Val-Trp; 
Ac-D-Phe-Leu-Asp-Ile-Chx-Trp; 
Ac-D-His-Leu-Asp-Ile-Chx-Trp; 
Ac-D-Trp-Leu-Asp-Ile-Chx-Trp; 
Ac-D-Tyr-Leu-Asp-Ile-Chx-Trp; 
Ac-D-Tyr(OMe)-Leu-Asp-Ile-Chx-Trp; 
Ac-D-Tyr(OEt)-Leu-Asp-Ile-Chx-Trp; 
Ac-D-2-Nal-Leu-Asp-Ile-Chx-Trp; 
Ac-D-1-Nal-Leu-Asp-Ile-Chx-Trp; 
Ac-D-Dip-Leu-Asp-Ile-Chx-Trp; 
Ac-D-Bip-Leu -Asp-Ile-Chx-Trp; 
Ac-D-Phe-Leu-Asp-Ile-Ile-2-Nal; 
Ac-D-His-Leu-Asp-Ile-Ile-2-Nal; 
Ac-D-Trp-Leu-Asp-Ile-Ile-2-Nal; 
Ac-D-Tyr-Leu-Asp-Ile-Ile-2-Nal; 
Ac-D-Tyr(OMe)-Leu-Asp-Ile-Ile-2-Nal; 
Ac-D-Tyr(OEt)-Leu-Asp-Ile-Ile-2-Nal; 
Ac-D-2-Nal-Leu-Asp-Ile-Ile-2-Nal; 
Ac-D-1-Nal-Leu-Asp-Ile-Ile-2-Nal; 
Ac-D-Dip-Leu-Asp-Ile-Ile-2-Nal; 
Ac-D-Bip-Leu-Asp-Ile-Ile-2-Nal; 
Ac-D-Phe-Leu-Asp-Ile-Ile-1-Nal; 
Ac-D-His-Leu-Asp-Ile-Ile-1-Nal; 
Ac-D-Tyr-Leu-Asp-Ile-Ile-1-Nal; 
Ac-D-Tyr-Leu-Asp-Ile-Ile-1-Nal; 
Ac-D-Tyr(OMe)-Leu-Asp-Ile-Ile-1-Nal; 
Ac-D-Tyr(OEt)-Leu-Asp-Ile-Ile-1-Nal; 
Ac-D-2-Nal-Leu-Asp-Ile-Ile-1-Nal; 
Ac-D-1-Nal-Leu-Asp-Ile-Ile-1-Nal; 
Ac-D-Dip-Leu-Asp-Ile-Ile-1-Nal; 
Ac-D-Bip-Leu-Asp-Ile-Ile-1-Nal; 
Ac-D-His-Leu-D-Asp-Ile-D-Ile-Trp; 
Ac-D-Phe-Leu-D-Asp-Ile-D-Ile-Trp; 
Ac-D-Bip-Leu-D-Asp-Ile-D-Ile-Trp; 
Ac-D-Dip-Leu-D-Asp-Ile-D-Ile-Trp; 
Ac-D-2-Nal-Leu-D-Asp-Ile-D-Ile-Trp; 
Ac-D-1-Nal-Leu-D-Asp-Ile-D-Ile-Trp; 
Ac-D-Trp-Leu-D-Asp-Ile-D-Ile-Trp; 
Ac-D-Dip-Asn-Ile-Ile-Trp; 
Ac-D-Dip-Phe-Ile-Ile-Trp; 
Ac-D-Dip-Ile-Ile-Trp; 
Ac-D-Dip-Asp-Ile-Ile-Trp; 
Ac-D-N-MeDip-Leu-Asp-Ile-Ile-Trp; 
Ac-D-Dip-Leu-Asp-Ile-Ile-N-MeTrp; 
Ac-D-Dip-Leu-Asp-Ile-N-MeIle-Trp; 
Ac-D-Dip-Leu-Asp-N-MeIle-Ile-Trp; 
Ac-D-Dip-Leu-N-MeAsp-Ile-Ile-Trp; 
Ac-D-Dip-N-MeLeu-Asp-Ile-Ile-Trp; 
Ac-D-Phe-Asp-Ile-Ile-Trp; 
Ac-D-His-Asp-Ile-Ile-Trp; 
Ac-D-Trp-Asp-Ile-Ile-Trp; 
Ac-D-Tyr-Asp-Ile-Ile-Trp; 
Ac-D-Tyr(OMe)-Asp-Ile-Ile-Trp; 
Ac-D-Tyr(OEt)-Asp-Ile-Ile-Trp; 
Ac-D-2-Nal-Asp-Ile-Ile-Trp; 
Ac-D-1-Nal-Asp-Ile-Ile-Trp; 
Ada-D-Phe-Asp-Ile-Ile-Trp; 
Ada-D-His-Asp-Ile-Ile-Trp; 
Ada-D-Trp-Asp-Ile-Ile-Trp; 
Ada-D-Tyr-Asp-Ile-Ile-Trp; 
Ada-D-Tyr(OMe)-Asp-Ile-Ile-Trp; 
Ada-D-Tyr(OEt)-Asp-Ile-Ile-Trp; 
Ada-D-2-Nal-Asp-Ile-Ile-Trp; 
Ada-D-1-Nal-Asp-Ile-Ile-Trp; 
Ada-D-Dip-Asp-Ile-Ile-Trp; 
Ada-D-Bip-Asp-Ile-Ile-Trp; 
Ac-D-Phe-Asp-Ile-Ile-2-Nal; 
Ac-D-Phe-Asp-Ile-Ile-1-Nal; 
Ac-D-His-Asp-Ile-Ile-2-Nal; 
Ac-D-His-Asp-Ile-Ile-1-Nal; 
Ac-D-Tyr-Asp-Ile-Ile-2-Nal; 
Ac-D-Tyr-Asp-Ile-Ile-1-Nal; 
Ac-D-Trp-Asp-Ile-Ile-2-Nal; 
Ac-D-Trp-Asp-Ile-Ile-1 -Nal; 
Ac-D-Dip-Asp-Ile-Ile-2 -Nal; 
Ac-D-Dip-Asp-Ile-Ile-1 -Nal; 
Ac-D-Bip-Asp-Ile-Ile-2 -Nal; 
Ac-D-Bip-Asp-Ile-Ile-1-Nal; 
Ac-D-Phe-Leu-Asp-Ile-Trp; 
Ac-D-His-Leu-Asp-Ile-Trp; 
Ac-D-Tyr-Leu-Asp-Ile-Trp; 
Ac-D-Dip-Leu-Asp-Ile-Trp; 
Ac-D-Trp-Leu-Asp-Ile-Trp; 
Ac-D-Phe-Leu-Asp-Ile-Ile-Trp-Gly; 
Ac-D-His-Leu-Asp-Ile-Ile-Trp-Gly; 
Ac-D-Trp-Leu-Asp-Ile-Ile-Trp-Gly; 
Ac-D-Tyr(OMe)-Leu-Asp-Ile-Ile-Trp-Gly; 
Ac-D-Tyr(OEt)-Leu-Asp-Ile-Ile-Trp-Gly; 
Ac-D-2-Nal-Leu-Asp-Ile-Ile-Trp-Gly; 
Ac-D-1-Nal-Leu-Asp-Ile-Ile-Trp-Gly; 
Ac-D-Dip-Leu-Asp-Ile-Ile-Trp-Gly; 
Ac-D-Bip-Leu-Asp-Ile-Ile-Trp-Gly; 
Ac-D-Phe-Leu-Asp-Ile-Ile-Trp-Asp; 
Ac-D-His-Leu-Asp-Ile-Ile-Trp-Asp; 
Ac-D-Trp-Leu-Asp-Ile-Ile-Trp-Asp; 
Ac-D-Tyr(OMe)-Leu-Asp-Ile-Ile-Trp-Asp; 
Ac-D-Tyr(OEt)-Leu-Asp-Ile-Ile-Trp-Asp; 
Ac-D-2-Nal-Leu-Asp-Ile-Ile-Trp-Asp; 
Ac-D-1-Nal-Leu-Asp-Ile-Ile-Trp-Asp; 
Ac-D-Dip-Leu-Asp-Ile-Ile-Trp-Asp; 
Ac-D-Dip-Leu-Asp-Ile-Ile-Trp-NH.sub.2 ; 
Ac-D-His-Leu-Asp-Ile-Ile-Trp; 
Bppa-Leu-Asp-Ile-Ile-Trp; 
Ada-D-Phe-Leu-Asp-Ile-Ile-Trp; 
Fmoc-D-Dip-Leu-Asp-Ile-Ile-Trp; 
Et-D-Dip-Leu-Asp-Ile-Ile-Trp; 
Bz-D-Dip-Leu-Asp-Ile-Ile-Trp; 
Pya-D-Dip-Leu-Asp-Ile-Ile-Trp; 
Cxl-D-Dip-Leu-Asp-Ile-Ile-Trp; 
Ada-D-Dip-Leu-Asp-Ile-Ile-Trp; 
Cxl(U)-D-Dip-Leu-Asp-Ile-Ile-Trp; 
Me(U)-D-Dip-Leu-Asp-Ile-Ile-Trp; 
tBu-D-Dip-Leu-Asp-Ile-Ile-Trp; 
CF.sub.3 CO-D-Dip-Leu-Asp-Ile-Ile-Trp; 
Ac-D-Chx-Leu-Asp-Ile-Ile-Trp; 
Ac-D-Dopa-Leu-Asp-Ile-Ile-Trp; 
D-Pmp-Leu-Asp-Ile-Ile-Trp; 
Ac-D-Pmp-Leu-Asp-Ile-Ile-Trp; 
D-Ana-Leu-Asp-Ile-Ile-Trp; 
Ac-D-Ana-Leu-Asp-Ile-Ile-Trp; 
Ac-D-Adm-Leu-Asp-Ile-Ile-Trp; 
Ac-D-Phe-Ala-Asp-Ile-Ile-Trp; 
Ac-D-Phe-Phe-Asp-Ile-Ile-Trp; 
Ac-D-Phe-D-Phe-Asp-Ile-Ile-Trp; 
Ac-D-Dip-D-Phe-Asp-Ile-Ile-Trp; 
D-Dip-Leu-Asn-Ile-Ile-Trp; 
Ac-D-Dip-Leu-Tyr-Ile-Ile-Trp; 
Ac-D-Phe-Leu-Asp-Ala-Ile-Trp; 
Ac-D-Dip-Leu-Asp-Glu-Ile-Trp; 
Ac-D-Dip-Leu-Asp-Phe-Ile-Trp; 
Ac-D-Dip-Leu-Asp-N-MeIle-Ile-Trp; 
Ac-D-Dip-Leu-Asp-Lys-Ile-Trp; 
Ac-D-Dip-Leu-Asp-Ala-Ile-Trp; 
Ac-D-Phe-Leu-Asp-Ile-Ala-Trp; 
Ac-D-Dip-Leu-Asp-Ile-Lys-Trp; 
Ac-D-Dip-Leu-Asp-Ile-Phe-Trp; 
Ac-D-Dip-Leu-Asp-Ile-Leu-Trp; 
Ac-D-Dip-Leu-Asp-Ile-Ile-Phe; 
Ac-D-Dip-Leu-Asp-Ile-Ile-Tyr; 
Ac-D-Phe-Leu-Asp-Ile-Ile-Tyr; 
Ac-D-Phe-Leu-Asn-Pro-Ile-Trp; 
Ac-D-Phe-Leu-Asp-Ala-Ile-Tyr; 
Ac-D-Dip-Leu-Asn-Pro-Ile-Trp; 
Ac-D-Phe-Asp-Phe-Ile-Trp; 
D-Dip-Tyr-Ile-Ile-Trp; 
Ac-D-Dip-Apa-Ile-Ile-Trp; 
Ac-D-Dip-D-Dip-Asp-Ile-Trp; and 
Ac-D-Dip-Ahp-Ile-Ile-Trp; 
or a pharmaceutically acceptable acid or base addition salt thereof. 
The compounds of Formula I are valuable antagonists of endothelin. The 
tests employed indicate that compounds of Formula I possess endothelin 
antagonist activity. 
Rat Heart Ventricle Binding Assay 
Thus, the compounds of Formula I were tested for their ability to inhibit 
[.sup.125 I]-ET-1([.sup.125 I]-Endothelin-1) binding in a receptor assay. 
The binding of the compounds of Formula I is determined by incubation 
(37.degree. C., 2 hours) of a compound of Formula I with .sup.25 I]-ET-1 
and the tissue (rat heart ventricle (10 .mu.g)) in 50 mM 
Tris(hydroxymethyl)aminomethane hydrochloride (Tris-HCl) (pH 7.4), 5 mM 
ethylenediamine tetraacetic acid (EDTA), 2 mM ethylene glycol 
bis(.beta.-aminoethyl ether)N,N,N',N'-tetraacetic acid (EGTA), 100 .mu.M 
phenylmethylsulfonyl fluoride (PMSF), and 100 .mu.M bacitracin containing 
protease inhibitors (total volume of 0.5 mL). IC.sub.50 values are 
calculated by weighing nonlinear regression curve-fitting to the 
mass-action (Langmuir) equation. 
Endothelin Receptor Binding Assay-A (ET.sub.A) Intact Cell Binding of 
[.sup.125 I]-ET-1 Materials and Terms Used: 
Cells 
The cells used were rabbit renal artery vascular smooth muscle cells grown 
in a 48-well dish (1 cm.sup.2) (confluent cells). 
Growth Media 
The growth media was Dulbeccos Modified Eagles/Ham's F12 which contained 
10% fetal bovine serum and antibiotics 
(penicillin/streptomycin/fungizone). 
Assay Buffer 
The assay buffer was a medium 199 containing Hank's salts and 25 mM Hepes 
buffer (Gibco 380-2350AJ), supplemented with 
penicillin/streptomycin/fungizone (0.5%) and bovine serum albumin (1 
mg/mL). 
8 .sup.125 I]-ET-1 
Amersham radioiodinated endothelin-1 [.sup.125 I]-ET-1 was used at final 
concentration of 20,000 cpm/0.25 mL (25 pM). 
Protocol 
First, add 0.5 mL warm assay buffer (described above) to the aspirated 
growth media and preincubate for 2 to 3 hours in a 37.degree. C. water 
bath (do not put back in the 5% carbon dioxide). Second, remove the assay 
buffers, place the dish on ice, and add 150 .mu.L of cold assay buffer 
described above to each well. Third, add 50 mL each of cold [.sup.125 
I]-ET-1 and competing ligand to the solution (at the same time if 
possible). Next, place dish in a 37.degree. C. water bath for about 2 
hours and gently agitate the dish every 15 minutes. Discard the 
radioactive incubation mixture in the sink and wash wells 3 times with 1 
mL of cold phosphate buffered saline. Last, add 250 mL of 0.25 M sodium 
hydroxide, agitate for 1 hour on rotator, and then transfer the sodium 
hydroxide extract to gamma counting tubes and count the radioactivity. 
Endothelin Receptor Binding Assay-B (ET.sub.B) [.sup.125 I]-ET-1 Binding in 
Rat Cerebellar Membranes Materials and Terms Used: 
Tissue Buffer 
The tissue is made up of 20 mM tris(hydroxymethyl)aminomethane 
hydrochloride (Trizma) buffer, 2 mM ethylenediaminetetraacetate, 100 .mu.M 
phenylmethylsulfonyl fluoride. 
Tissue Preparation 
First, thaw one aliquot of frozen rat cerebellar membranes (2 mg protein in 
0.5 mL). Next, add 0.5 mL membrane aliquot to 4.5 mL cold tissue buffer, 
polytron at 7,500 revolutions per minute for 10 seconds. Finally, dilute 
tissue suspension 1/100 (0.1 mL suspension+9.9 mL tissue buffer), polytron 
again, and place ice. 
Dilution Buffer 
Medium 199 with Hank's salts plus 25 mM Hepes+1 mg/mL bovine serum albumin. 
[.sup.125 I]-ET-1 
Amersham [.sup.125 I]-ET-1 (aliquots of 2.times.10.sup.6 cpm per 100 mL 
aliquot of [.sup.125 I]-ET-1 with 5.2 mL dilution buffer, place on ice 
until use (final concentration will be 20,000 cpm per tube, or 25 pM). 
Protocol 
Add 50 .mu.L each of cold [.sup.125 I]-ET-1 and competing ligand to tubes 
on ice. Mix in 150 .mu.L of tissue to each tube, vortex briefly, then tap 
to force all liquids to bottom (total assay volume=250 .mu.L). Then place 
the tubes in a 37.degree. C. water bath for 2 hours. 
Add 2.5 mL cold water buffer (50 mM Trizma buffer) to each tube, filter, 
and then wash tube with additional 2.5 mL wash buffer and add to filter. 
Finally, wash filters with an additional 2.5 mL of cold wash buffer. 
Count filters for radioactivity in gamma counter. 
Inositol Phosphate Accumulation 
The functional activity of compounds of Formula I is determined in Rat-1 
cells by measuring intracellular levels of second messengers. Thus, cells 
were prelabeled with [.sup.3 H]-inositol and endothelin-stimulated 
accumulation of total [3H]-inositol phosphates in the presence of Li.sup.+ 
is monitored using anion exchange chromatography as described by Muldoon, 
L. L., et al, Journal of Biological Chemistry, Volume 264, pages 8529-8536 
(1989) and Dudley, D. T., et al, Molecular Pharmacology, Volume 38, pages 
370-377 (1990). Antagonist activity is assessed as the ability of added 
compounds to reduce endothelin-stimulated inositol phosphate accumulation. 
Arachidonic Acid Release Assay 
Antagonist activity was also measured by the ability of added compounds to 
reduce endothelin-stimulated arachidonic acid release (AAR) in cultured 
vascular smooth muscle cells as described in Reynolds, E., Mok, L., FASEB 
J., 1991, 5, A1066. 
Briefly, antagonist activity is measured by the ability of added compounds 
to reduce endothelin-stimulated arachidonic acid release in cultured 
vascular smooth muscle cells as arachidonic acid release. [.sup.3 H] 
Arachidonic Acid Loading Media (LM) is DME/F12+0.5% FCS.times.0.25 mCi/mL 
[.sup.3 H] arachidonic acid (Amersham). Confluent monolayers of cultured 
rabbit renal artery vascular smooth muscle cells were incubated in 0.5 mL 
of the LM over 18 hours, at 37.degree. C., in 5% CO.sub.2. The LM was 
aspirated and the cells were washed once with the assay buffer (Hank's 
BSS+10 mM HEPES+fatty acid-free BSA (1 mg/mL), and incubated for 5 minutes 
with 1 mL of the prewarmed assay buffer. This solution was aspirated, 
followed by an additional 1 mL of prewarmed assay buffer, and further 
incubated for another 5 minutes. A final 5-minute incubation was carried 
out in a similar manner. The same procedure was repeated with the 
inclusion of 10 .mu.L of the test compound (1 nM to 1 .mu.M) and 10 .mu.L 
ET-1 (0.3 nM) and the incubation was extended for 30 minutes. This 
solution was then collected, 10 .mu.L of scintillation cocktail was added, 
and the amount of [.sup.3 H] arachidonic acid was determined in a liquid 
scintillation counter. 
The data in Table II and IIa below show the endothelin antagonist activity 
of representative compounds of Formula I. 
TABLE II 
__________________________________________________________________________ 
Biological Activity of Compounds of Formula I 
Binding Assay in 
IP (Inositol 
Rat Heart 
Phosphate) 
Ventricle IC.sub.50 
Accumulation 
Example (.mu.M) or % 
IC.sub.50 (.mu.M) or % 
AAR 
Number 
Compound Inhibition 
Inhibition 
IC.sub.50 (.mu.M) 
__________________________________________________________________________ 
1 Ac-D-Phe--Leu--Asp--Ile--Ile--Trp 
0.72 0.86 
4 D-2-Nal--Leu--Asp--Ile--Ile--Trp 
8.98 53% @ 50 .mu.M 
5 Ac-D-2-Nal--Leu--Asp--Ile--Ile--Trp 
1.63 0.63 1.9 
6 Ac-D-Phe--Leu--Asp--Ile--Trp 
24.5 
7 Ac-D-His--Leu-D-Asp--Ile-D-Ile--Trp 
6.03 
8 Ac-D-Phe--Orn--Asp--Ile--Ile--Trp 
0.68 0.43 
9 Ac-D-Phe--Glu--Asp--Ile--Ile--Trp 
0.74 0.60 
10 Ac-D-Tyr--Leu--Asp--Ile--Ile--Trp 
0.70 0.43 0.25 
11 Ac-D-Phe--Asp--Ile--Ile--Trp 
2.15 
12 Fmoc-D-Phe--Leu--Asp--Ile--Ile--Trp 
0.43 
13 Ac-D-Dip--Leu--Asp--Ile--Ile--Trp 
0.015 0.07 
16 Ac-D-Dip--Leu--Phe--Ile--Ile--Trp 
0.047 1.8 
17 Ac-D-Dip--Leu--Asp--Ile--Lys--Trp 
24.6% @ 10 .mu.M 
18 Ac-D-Dip--Leu--Asp--Ile--Glu--Trp 
37.0% @ 10 .mu.M 
19 Ac-D-Dip--Leu--Asp--Glu--Ile--Trp 
0.015 
20 Ac-D-Dip--Glu--Asp--Ile--Ile--Trp 
0.085 
21 Ac-D-Dip--Orn--Asp--Ile--Ile--Trp 
79% @ 0.05 .mu.M 
0.02 
23 Ac-D-Dip-D-Leu--Asp--Ile--Ile--Trp 
41.3% @ 10 .mu.M 
__________________________________________________________________________ 
TABLE IIa 
__________________________________________________________________________ 
Biological Activity of Compounds of Formula I 
Binding Assay IC.sub.50 (.mu.M) 
IP (Inositol Phosphate) 
% Inhibition at Receptor 
Accumulation, IC.sub.50 
Example Subtypes (.mu.M) or % 
AAR 
Number 
Compound ET.sub.A 
ET.sub.B 
Inhibition IC.sub.50 
__________________________________________________________________________ 
(.mu.M) 
24 Ac-D-Dip--Leu--Asp--Ile--Ile--Trp--NH.sub.2 
0.32 5.0 6.0 
25 Ac-D-His--Leu--Asp--Ile--Ile--Trp 
9.5 10.0 1.4 3.2 
26 Ac-D-Dip-D-Leu--Asp--Ile--Ile--Trp 
3.0 2.0 3.68 
27 Ac-D-Dip--Leu--Asn--Pro--Ile--Trp 
0.73 0.62 8.4 
28 Bppa--Leu--Asp--Ile--Ile--Trp 
8.0 1.7 5.6 
29 Ada-D-Phe--Leu--Asp--Ile--Ile--Trp 19.7 
30 Fmoc-D-Dip--Leu--Asp--Ile--Ile--Trp 
6.0 6.0 2.6 
31 Et-D-Dip--Leu--Asp--Ile--Ile--Trp 
1.8 2.0 
32 Bz-D-Dip--Leu--Asp--Ile--Ile--Trp 
4.6 0.03 
33 Pya-D-Dip--Leu--Asp--Ile--Ile--Trp 
5.0 0.18 
34 Cxl-D-Dip--Leu--Asp--Ile--Ile--Trp 
3.4 0.20 
35 Ada-D-Dip--Leu--Asp--Ile--Ile--Trp 
4.0 0.5 
36 Cxl(U)-D-Dip--Leu--Asp--Ile--Ile--Trp 
0.82 0.05 
37 Me(U)-D-Dip--Leu--Asp--Ile--Ile--Trp 
1.0 1.5 
38 tBu-D-Dip--Leu--Asp--Ile--Ile--Trp 
10 0.5 
39 CF.sub.3 CO-D-Dip--Leu--Asp--Ile--Ile--Trp 
0.25 0.9 
40 Ac-D-Phe--Leu--Asp--Ile--Ile--Trp 
2.8 3.3 1.18 3.1 
41 Ac-D-Tyr--Leu--Asp--Ile--Ile--Trp 
0.40 7.0 0.43 0.25 
42 Ac-D-Chx--Leu--Asp--Ile--lle--Trp 
2.3 1.1 
43 Ac-D-Tyr(OMe)--Leu--Asp--Ile--Ile--Trp 
2.1 &gt;10 6.2 
44 2-D-Nal--Leu--Asp--Ile--Ile--Trp 53% @ 50 .mu.M 
45 Ac-1-D-Nal--Leu--Aap--Ile--Ile--Trp 
0.30 0.45 
46 Ac-2-D-Nal--Leu--Asp--Ile--Ile--Trp 
1.0 4.0 0.63 1.9 
47 Ac-D-Dopa--Leu--Asp--Ile--Ile--Trp 
7.0 &gt;10 
48 Ac-D-Trp--Leu--Asp--Ile--Ile--Trp 
0.13 1.8 0.45 
49 D-Dip--Leu--Asp--lle--Ile--Trp 
2.1 1.9 1.92 
50 Ac-D-Dip--Leu--Asp--Ile--Ile--Trp 
0.015 0.15 0.0145 0.07 
51 Ac-D-Bip--Leu--Asp--Ile--Ile--Trp 
4.4 3.5 6.0 
52 D-Pmp--Leu--Asp-- Ile--Ile--Trp 
6.0 3.87 
53 Ac-D-Pmp--Leu--Asp--Ile--Ile--Trp 
1.5 5.5 
54 D-Ana--Leu--Asp--lle--Ile--Trp 
5.86 1.21 
55 Ac-D-Ana--Leu--Asp--Ile--Ile--Trp 
0.54 0.79 
56 Ac-D-Adm--Leu--Asp--Ile--Ile--Trp 
3.22 1.92 
57 Ac-D-Phe--Glu--Asp--Ile--Ile--Trp 
0.65 1.3 0.60 
58 Ac-D-Phe--Orn--Asp--Ile--Ile--Trp 
0.70 4.0 0.43 2.0 
59 Ac-D-Phe--Ala--Asp--Ile--Ile--Trp 
0.40 0.30 0.3 0.33 
60 Ac-D-Phe--Phe--Asp--Ile--Ile--Trp 
0.20 0.30 2.6 
61 Ac-D-Phe-D-Phe--Asp--Ile--Ile--Trp 
0.8 0.01 2.7 
62 Ac-D-Dip--Glu--Asp--Ile--Ile--Trp 
0.025 0.052 0.13 
63 Ac-D-Dip--Orn--Asp--Ile--Ile--Trp 
0.015 0.22 0.02 
64 Ac-D-Dip-D-Phe--Asp--Ile--Ile--Trp 
0.38 0.74 0.32 
65 Ac-D-Dip--N--MeLeu--Asp--Ile--Ile--Trp 
0.20 0.60 
66 Ac-D-Dip--Arg--Asp--Ile--Ile--Trp 
0.004 0.010 
67 Ac-D-Phe--Leu--Phe--Ile--Ile--Trp 
1.18 0.035 4.5 
68 Ac-D-Dip--Leu--Phe--Ile--Ile--Trp 
1.0 0.008 1.8 
69 Ac-D-Dip--Leu--Lys--Ile--Ile--Trp 
0.48 0.033 0.98 
70 D-Dip--Leu--Asn--Ile--Ile-- Trp 
6.43 0.833 
71 Ac-D-Dip--Leu--Glu--Ile--Ile--Trp 
0.021 0.019 0.43 
72 Ac-D-Dip--Leu--Tyr--Ile--Ile--Trp 
0.50 0.080 
73 Ac-D-Phe--Leu--Asp--Ala--Ile--Trp 
3.50 0.33 1.50 
74 Ac-D-Dip--Leu--Asp--Glu--Ile--Trp 
1.0 6.0 0.45 
75 Ac-D-Dip--Leu--Asp--Chx--Ile--Trp 
0.065 0.21 0.15 
76 Ac-D-Dip--Leu--Asp--Phe--Ile--Trp 
0.11 0.05 
77 Ac-D-Dip--Leu--Asp--N--MeIle--Ile--Trp 
0.68 &gt;1 1.9 
78 Ac-D-Dip--Leu--Asp--Phe--Ile--Trp 
0.24 0.065 0.3 
79 Ac-D-Dip--Leu--Asp--Lys--Ile--Trp 
&gt;10 3.7 &gt;10 
80 Ac-D-Dip--Leu--Asp--Ala--Ile--Trp 
0.1 0.33 0.42 
81 Ac-D-Dip--Leu--Asp--Val--Ile--Trp 
0.015 0.08 0.034 
82 Ac-D-Phe--Leu--Asp--Ile--Ala--Trp 
8.0 &gt;1.0 &gt;10 
83 Ac-D-Dip--Leu--Asp--Ile--Lys--Trp 
&gt;10 4.2 
84 Ac-D-Dip--Leu--Asp--Ile--Phe--Trp 
4.0 7.5 &gt;10 
85 Ac-D-Dip--Leu--Asp--Ile--Leu--Trp 
0.23 0.73 0.12 
86 Ac-D-Dip--Leu--Asp--Ile--Val--Trp 
0.097 0.63 
87 Ac-D-Dip--Leu--Asp--Ile--Ile--Phe 
5.0 6.8 &gt;10 
88 Ac-D-Dip--Leu--Asp--Ile--Ile--Tyr 
3.7 6.3 4.3 
89 Ac-D-Phe--Leu--Asp--Ile--Ile--Tyr 
&gt;10 0.22 
90 Ac-D-Phe--Leu--Asn--Pro--Ile--Trp 
1.98 2.8 0.11 
91 Ac-D-Phe--Leu--Asp--Ala--Ile--Tyr 
&gt;10 &gt;10 8.4 
92 Ac-D-Phe--Asp--Ile--Ile--Trp 
9.1 9.3 30% @ 10 .mu.M 
93 Ac-D-Phe--Asp--Phe--Ile--Trp 
37.4% @ 10 .mu.M 
64.7% @ 10 .mu.M 
94 Ac-D-Dip--Asp--Ile--Ile--Trp 
&gt;1.0 0.25 3.2 
95 D-Dip--Tyr--Ile--Ile--Trp 
8.0 0.35 3.90 
96 Ac-D-Dip--Apa--Ile--Ile--Trp 
&gt;10 3.98 &gt;10 
97 Ac-D-Dip--Leu--Asp--Ile--Trp 
1.5 2.1 
98 Ac-D-Dip-D-Dip--Asp--Ile--Trp 
7.87 &gt;10 
99 Ac-D-Dip--Ahp--Ile--Ile--Trp 
4.09 1.86 
__________________________________________________________________________ 
In Vitro (Isolated Vessel) Studies 
Male New Zealand rabbits were killed by cervical dislocation and 
exsanguination. Femoral and pulmonary arteries were isolated, cleaned of 
connective tissue, and cut into 4 mm rings. The endothelium was denuded by 
placing the rings over hypodermic tubing (32 gauge for femoral rings and 
28 gauge for pulmonary rings, Small Parts Inc., Miami, Fla.) and gently 
rolling them. Denuded rings were mounted in 20 mL organ baths containing 
Krebs-bicarbonate buffer (composition in mM: NaCl, 118.2; NaHCO.sub.3, 
24.8; KCl, 4.6; MgSO.sub.4, 7.H.sub.2 O, 1.2; KH.sub.2 PO.sub.4, 1.2; 
CaCl.sub.2.2H.sub.2 O; Ca-Na.sub.2 EDTA, 0.026; Dextrose, 10.0), that was 
maintained at 37.degree. C., and gassed continuously with 5% CO.sub.2 in 
oxygen (pH 7.4). Resting tension was adjusted to 3.0 g for femoral and 4.0 
g pulmonary arteries; the rings were left for 90 minutes to equilibrate. 
Tension was monitored with force displacement transducers (Grass FT03, 
Quincy, Mass.) and recorded on a polygraph (Gould 2108, Cleveland, Ohio) 
recorder. 
Vascular rings were tested for a lack of functional endothelium, i.e., lack 
of an endothelium-dependent relaxation response to carbachol (1.0 .mu.M) 
in norepinephrine (0.03 .mu.M) contracted rings. Agonist peptides, ET-1, 
for femoral artery rings and SRTX-6c for pulmonary artery rings (one 
peptide per experiment), were cumulatively added at 10-minute intervals. 
In separate experiments, the test compounds (ET antagonists), were added 
30 minutes prior to adding the agonist as indicated above. 
For the in vitro experiments compounds were dissolved in 0.1% acetic acid 
in distilled water. The maximum concentration of DMSO in the bath was 0.1% 
which did not significantly affect developed tension in response to ET-1, 
ET-3, or SRTX-6c. The antagonist activity of various compounds are 
expressed as pA.sub.2 values in Table III. 
__________________________________________________________________________ 
pA.sub.2 Values 
Example Rat Femoral 
Rat Pulmonary 
Number 
Compound Artery Artery 
__________________________________________________________________________ 
1 Ac-D-Dip--Leu--Asp--Ile--Ile--Trp.2Na.sup.+ 
6.56 6.26 
2 Ac-D-Dip--Glu--Asp--Ile--Ile--Trp 
6.09 6.85 
3 Ac-D-Dip--Arg--Asp--Ile--Ile--Trp 
6.33 5.68 
4 Ac-D-Dip--Leu--Asp--Phe--Ile--Trp 
-- 5.84 
__________________________________________________________________________ 
In Vivo Studies 
Male Sprague Dawley rats (300 to 500 g) were anesthetized (Inactin, 120 
mg/kg IP) and acutely instrumented for measurement of systemic 
hemodynamics. Cannulae (PE 50) were placed in the left carotid artery to 
measure mean arterial blood pressure (MABP) and left and right jugular 
veins for drug administration. The trachea was cannulated (PE 240) for 
artificial respiration (Harvard Apparatus, Model 681, South Natick, Mass.) 
at a rate of 100 cycles/min and a tidal volume of 3.0 mL/kg. Cardiac 
output was measured using a thoracic aortic flow probe (Transonics, probe 
size 1RB, Ithaca, N.Y.). 
In separate experiments regional hemodynamics were assessed. To monitor 
regional blood flow rats were similarly anesthetized and instrumented for 
measurement of MABP and intravenous (IV) drug administration. The trachea 
was cannulated and the rats were allowed to breathe spontaneously. In 
addition, flow probes (Transonics, probe size 1RB, Ithaca, N.Y.) were 
placed on the left renal, left iliac, right carotid, and/or mesenteric 
arteries. All rats were ganglionic blocked with mecamylamine (1.25 mg/kg, 
IV) to block hemodynamic reflexes and allowed to stabilize for 5 minutes. 
Responses to rising doses (0.03, 0.1, 0.3, 1.0, and 3.0 nmol/kg, IV bolus) 
of ET-1 or SRTX-6c were measured continuously and averaged at 1-second 
intervals during the depressor phase and at 5-second intervals during the 
pressor phase. Agonists were administered at 5-minute intervals. Changes 
in SVR and regional vascular resistances were calculated for individual 
rats based on blood flow and arterial blood pressure measurements at the 
peak of depressor and pressor responses. The effects of test compounds (ET 
antagonists) on the hemodynamic responses to ET-1 and S6c were determined 
in separate experiments. Infusion of the test compounds (1.0 .mu.mol/kg/5 
min) were initiated 5 minutes prior to the first ET-1 or SRTX-6c challenge 
and maintained throughout the agonist dose response curve. Data points for 
global and regional hemodynamics represent the mean of four to eight rats. 
For in vivo experiments compounds were dissolved in 0.1% acetic acid in 
distilled water. 
To determine in vivo endothelin antagonism by Ac-D-Dip-Leu-Asp-Ile-Ile-Trp, 
male Sprague Dawley rats (300-500 g) were anesthetized (Inactin, 120 
mg/kg, IP) and instrumented to measure mean arterial blood pressure, and 
renal and hind limb blood flow. Ganglionic blockade (mecamylamine, 1.25 
mg/kg, IV) was produced to prevent hemodynamic reflexes. ET-1 (0.3-3.0 
nM/kg, IV bolus 5 minutes apart) caused transient dose dependent depressor 
responses followed by slowly (.about.2 minutes to max.) developing 
pressure responses. Predominant vasodilator responses to ET-1 were 
observed in the hind limb versus predominant vasoconstrictor responses in 
the renal bed. Pretreatment with Ac-D-Dip-Leu-Asp-Ile-Ile-Trp (1.0 
.mu.M/kg/5 minutes, IV infusion) significantly attenuated the systemic 
depressor responses to ET-1, but had no effect on pressor responses. In 
the regional beds, pretreatment with Ac-D-Dip-Leu-Asp-Ile-Ile-Trp 
significantly attenuated (.about.50%) the vasodilatation to ET-1 in the 
hind limb, whereas the vasoconstriction to ET-1 in the renal bed was 
unchanged. 
As in vivo test bases on the peak effect of single bolus doses of ET 
antagonists on depressor and pressor responses to ET has been developed in 
conscious rats. This model is able to provide both potency and duration of 
action information. Duration of action studies were carried out in the 
conscious chronically prepared normotensive rats with a 5-day treatment 
protocol. There were 5 groups of animals with dosing regimen of drug at 
(10 .mu.M/kg IV bolus) 0, 5, 20, 60, and 120 minutes before the ET-1 
challenge. In the control set of animals vehicle was administered instead 
of drug. There was no repetitive dosing of ET-1 due to the inability to 
wash out the response. These studies were carried out with the ET 
antagonist Ac-D-Dip-Leu-Asp-Ile-Ile-Trp. The results indicate that 
Ac-D-Dip-Leu-Asp-Ile-Ile-Trp showed blocking of the depressor component of 
the ET-1 challenge 2 hours postdose. 
Statistics 
An F test for parallelism was used to evaluate the effects of antagonist 
pretreatment on the contractile activity of ET-1 in isolated vessels. 
Statistical differences between parallel curves were determined using 
t-test on EC.sub.50 values. An F test was used to assess significant 
differences among treatment groups for systemic and regional hemodynamic 
parameters. 
Paired t-tests, corrected for multiple comparison with the Bonferroni 
inequality adjustment, were used to determine significant differences from 
control values within treatment groups. 
General Method for Preparing Compounds of Formula I 
The compounds of Formula I may be prepared by solid phase peptide synthesis 
on a peptide synthesizer, for example, an Applied Biosystems 430A peptide 
synthesizer using activated esters or anhydrides of N-alpha-Boc protected 
amino acids, on PAM or FIBHA resins. Additionally, the compounds of 
Formula I may also be prepared by conventional solution peptide synthesis. 
Amino acid side chains are protected as follows: Bzl(Asp, Glu, Ser), 
2-Cl-Z(Lys), 2-Br-Z(Tyr), Bom(His), For(Trp), and MeBzl(Cys). Each peptide 
resin (1.0 g) is cleaved with 9 mL of HF and 1 mL of anisole or p-cresol 
as a scavenger (60 minutes, 0.degree. C.). The peptide resin is washed 
with cyclohexane, extracted with 30% aqueous HOAc, followed by glacial 
HOAc, concentrated under reduced pressure, and lyophilized. (A peptide 
containing For(Trp) is dissolved in water at 0.degree. C., the pH is 
adjusted to 12.5 with 1N KOH (2 minutes), neutralized with glacial HOAc, 
desalted on C.sub.18 (as described below), and lyophilized. The crude 
peptide is purified by preparative reversed phase high performance liquid 
chromatography (RP-HPLC) on a C.sub.18 column (2.2.times.25.0 cm, 15.0 
mL/min) with a linear gradient of 0.1% TFA in water to 0.1% TFA in 
acetonitrile and lyophilized. The homogeneity and composition of the 
resulting peptide is verified by RP-HPLC, capillary electrophoresis, thin 
layer chromatography (TLC), proton nuclear magnetic resonance spectrometry 
(NMR), and fast atom bombardment mass spectrometry (FAB-MS). 
The compounds of the present invention can be prepared and administered in 
a wide variety of oral and parenteral dosage forms. Thus, the compounds of 
the present invention can be administered by injection, that is, 
intravenously, intramuscularly, intracutaneously, subcutaneously, 
intraduodenally, or intraperitoneally. Also, the compounds of the present 
invention can be administered by inhalation, for example, intranasally. 
Additionally, the compounds of the present invention can be administered 
transdermally. It will be obvious to those skilled in the art that the 
following dosage forms may comprise as the active component, either a 
compound of Formula I or a corresponding pharmaceutically acceptable salt 
of a compound of Formula I. 
For preparing pharmaceutical compositions from the compounds of the present 
invention, pharmaceutically acceptable carriers can be either solid or 
liquid. Solid form preparations include powders, tablets, pills, capsules, 
cachets, suppositories, and dispersible granules. A solid carrier can be 
one or more substances which may also act as diluents, flavoring agents, 
binders, preservatives, tablet disintegrating agents, or an encapsulating 
material. 
In powders, the carrier is a finely divided solid which is in a mixture 
with the finely divided active component. 
In tablets, the active component is mixed with the carrier having the 
necessary binding properties in suitable proportions and compacted in the 
shape and size desired. 
The powders and tablets preferably contain from five or ten to about 
seventy percent of the active compound. Suitable carriers are magnesium 
carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, 
starch, gelatin, tragacanth, methylcellulose, sodium 
carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The 
term "preparation" is intended to include the formulation of the active 
compound with encapsulating material as a carrier providing a capsule in 
which the active component with or without other carriers, is surrounded 
by a carrier, which is thus in association with it. Similarly, cachets and 
lozenges are included. Tablets, powders, capsules, pills, cachets, and 
lozenges can be used as solid dosage forms suitable for oral 
administration. 
For preparing suppositories, a low melting wax, such as a mixture of fatty 
acid glycerides or cocoa butter, is first melted and the active component 
is dispersed homogeneously therein, as by stirring. The molten homogenous 
mixture is then poured into convenient sized molds, allowed to cool, and 
thereby to solidify. 
Liquid form preparations include solutions, suspensions, and emulsions, for 
example, water or water propylene glycol solutions. For parenteral 
injection liquid preparations can be formulated in solution in aqueous 
polyethylene glycol solution. 
Aqueous solutions suitable for oral use can be prepared by dissolving the 
active component in water and adding suitable colorants, flavors, 
stabilizing and thickening agents as desired. 
Aqueous suspensions suitable for oral use can be made by dispersing the 
finely divided active component in water with viscous material, such as 
natural or synthetic gums, resins, methylcellulose, sodium 
carboxymethylcellulose, and other well-known suspending agents. 
Also included are solid form preparations which are intended to be 
converted, shortly before use, to liquid form preparations for oral 
administration. Such liquid forms include solutions, suspensions, and 
emulsions. These preparations may contain, in addition to the active 
component, colorants, flavors, stabilizers, buffers, artificial and 
natural sweeteners, dispersants, thickeners, solubilizing agents, and the 
like. 
The pharmaceutical preparation is preferably in unit dosage form. In such 
form the preparation is subdivided into unit doses containing appropriate 
quantities of the active component. The unit dosage form can be a packaged 
preparation, the package containing discrete quantities of preparation, 
such as packeted tablets, capsules, and powders in vials or ampoules. 
Also, the unit dosage form can be a capsules, tablet, cachet, or lozenge 
itself, or it can be the appropriate number of any of these in packaged 
form. 
The quantity of active component in a unit dose preparation may be varied 
or adjusted from 0.1 mg to 100 mg preferably 0.5 mg to 100 mg according to 
the particular application and the potency of the active component. The 
composition can, if desired, also contain other compatible therapeutic 
agents. 
In therapeutic use as antagonist of endothelin, the compounds utilized in 
the pharmaceutical method of this invention are administered at the 
initial dosage of about 0.01 mg to about 20 mg per kilogram daily. A daily 
dose range of about 0.01 mg to about 10 mg per kilogram is preferred. The 
dosages, however, may be varied depending upon the requirements of the 
patient, the severity of the condition being treated, and the compound 
being employed. Determination of the proper dosage for a particular 
situation is within the skill of the art. Generally, treatment is 
initiated with smaller dosages which are less than the optimum dose of the 
compound. Thereafter, the dosage is increased by small increments until 
the optimum effect under the circumstances is reached. For convenience, 
the total daily dosage may be divided and administered in portions during 
the day, if desired. 
The following nonlimiting examples illustrate the inventors' preferred 
methods for preparing the compounds of the invention. 
EXAMPLE 1 
Ac-D-Phe-Leu-Asp-Ile-Ile-Trp 
The linear hexapeptide is prepared by standard solid phase synthetic 
peptide methodology utilizing a Boc/benzyl strategy (Stewart, J. M. and 
Young, J. D., Solid Phase Peptide Synthesis, Pierce Chemical Co., 
Rockford, Ill., 1984). All protected amino acids and reagents are obtained 
from commercial sources and are not further purified. The protected 
peptide resin is prepared on an Applied Biosystems 430A Peptide 
Synthesizer, utilizing protocols supplied for a dicyclohexylcarbodiimide 
mediated coupling scheme (Standard 1.0, Version 1.40). Starting with 0.560 
g of N-.alpha.-Boc-Trp(For)-PAM resin (0.88 meq/g, 0.43 meq of 
Boc-Trp(For) total) the protected peptide is prepared by the stepwise 
coupling of the following amino acids (in order of addition): 
N-.alpha.-Boc-D-Phe, N-.alpha.-Boc-Leu.H.sub.2 O, N-.alpha.-Boc-Asp(Bzl), 
and N-.alpha.-Boc-Ile,0.5 H.sub.2 O. A typical cycle for the coupling of 
an individual amino acid residue is illustrated below (reproduced from the 
ABI manual): 
All the single couple RV cycles conform to the following pattern: 
1) 33% TFA in DCM for 80 seconds 
2) 50% TFA in DCM for 18.5 minutes 
3) Three DCM washes 
4) 10% DIEA in DMF for 1 minute 
5) 10% DIEA in DMF for 1 minute 
6) Five DMF washes 
7) Coupling period 
8) five DCM washes 
After the coupling of N-.alpha.-Boc-D-Phe, the Boc group is removed with 
the end-NH.sub.2 cycle and the free amine is acetylated with 
N-acetylimidazole (1.0 g, 120 minutes) in 20 mL of dichloromethane (DCM). 
The resin is washed with DCM (3.times.20 mL) and dried under reduced 
pressure (0.878 g). 
The peptide is liberated from the solid support, and the carboxylate of 
aspartic acid deprotected by treatment with anhydrous hydrogen fluoride 
(9.0 mL), anisole (1.0 mL), and dimethyl sulfide (0.5 mL) (60 minutes, 
0.degree. C.). After removing the hydrogen fluoride under a stream of 
nitrogen, the resin is washed with diethyl ether (3.times.30 mL) and 
extracted with 20% HOAc in water (3.times.30 mL) and glacial HOAc 
(2.times.30 mL). The aqueous extractions are combined, concentrated under 
reduced pressure, and lyophilized (320 mg). To remove the formyl 
protecting group, the crude peptide is suspended in 50 mL of aqueous 0.1 N 
KOH at 0.degree. C. for 2 minutes. The pH of the solution is adjusted to 
less than 4.0 with 10% HCl/H.sub.2 O and passed through a C 18 (60 cc) 
cartridge. The cartridge is washed with H.sub.2 O (50 mL), eluted with 
0.1% TFA, 70% CH.sub.3 CN in H.sub.2 O, the eluants combined, concentrated 
under reduced pressure (10 mL), diluted with H.sub.2 O, and lyophilized to 
yield 153 mg of a white powder. The crude peptide is dissolved in 4.0 mL 
of 50% TFA/H.sub.2 O, filtered through a 0.4 .mu.M syringe filter, and 
chromatographed on a Vydac 218TP 1022 column (2.2.times.25.0 cm, 15.0 
mL/min, A: 0.1% TFA/H.sub.2 O, B: 0.1% TFA/CH.sub.3 CN, Gradient; 0% B for 
10 minutes, 10% to 50% B over 120 minutes). Individual fractions are 
collected and combined based upon analysis by analytical HPLC. The 
combined fractions are concentrated under reduced pressure (10 mL), 
diluted with H.sub.2 O (50 mL), and lyophilized (14.8 mg). The homogeneity 
and structure of the resulting peptide is confirmed by analytical HPLC, 
capillary zone electrophoresis, Proton Nuclear Magnetic Resonance 
Spectroscopy (H.sup.1 -NMR) and Fast Atom Bombardment Mass Spectroscopy 
(FAB-MS), MH.sup.+ 848.4. 
In a process analogous to Example 1 using the appropriate amino acids, the 
corresponding compounds of Formula I are prepared as follows: 
EXAMPLE 2 
D-2-Nal-Leu-Asp-Ile-Ile-Trp; FAB-MS, MH.sup.+ 856.3. 
EXAMPLE 3 
Ac-D-2-Nal-Leu-Asp-Ile-Ile-Trp; FAB-MS, MH.sup.+ 898.5. 
EXAMPLE 4 
D-1-Nal-Leu-Asp-Ile-Ile-Trp; MH.sup.+ 856.3, MNa.sup.+ 878.2. 
EXAMPLE 5 
Ac-D-1-Nal-Leu-Asp-Ile-Ile-Trp; MH.sup.+ 898.5, MNa.sup.+ 920.5. 
EXAMPLE 6 
Ac-D-Phe-Leu-Asp-Ile-Trp; MH.sup.+ 735.5, MNa.sup.+ 757.8. 
EXAMPLE 7 
Ac-D-His-Leu-D-Asp-Ile-D-Ile-Trp; MH.sup.+ 838.5, MNa.sup.+ 860.40. 
EXAMPLE 8 
Ac-D-Phe-Orn-Asp-Ile-Ile-Trp; MH.sup.+ 849.1, MNa.sup.+ 871.0. 
EXAMPLE 9 
Ac-D-Phe-Glu-Asp-Ile-Ile-Trp; MH.sup.+ 864.1, MNa.sup.+ 886.0. 
EXAMPLE 10 
Ac-D-Tyr-Leu-Asp-Ile-Ile-Trp; MH.sup.+ 864.0, MNa.sup.+ 886.3. 
EXAMPLE 11 
Ac-D-Phe-Asp-Ile-Ile-Trp; MH.sup.+ 735.1, MNa.sup.+ 757.3. 
EXAMPLE 12 
Fmoc-D-Phe-Leu-Asp-Ile-Ile-Trp; MH.sup.+ 1028.1, MNa.sup.+ 1050.3. 
EXAMPLE 13 
Ac-D-Dip-Leu-Asp-Ile-Ile-Trp; FAB-MS, MNa.sup.+ 946.6. 
EXAMPLE 14 
Ac-D-Dip-Ile-Ile-Trp; FAB-MS, MH.sup.+ 696.5, MNa.sup.+ 718.5. 
EXAMPLE 15 
Ac-D-Dip-Asp-Ile-Ile-Trp; FAB-MS, MH.sup.+ 810.4, MNa.sup.+ 833.5. 
EXAMPLE 16 
Ac-D-Dip-Leu-Phe-Ile-Ile-Trp; FAB-MS, MNa.sup.+ 978.3. 
EXAMPLE 17 
Ac-D-Dip-Leu-Asp-Ile-Lys-Trp; FAB-MS, MH.sup.+ 939.6. 
EXAMPLE 18 
Ac-D-Dip-Leu-Asp-Ile-Glu-Trp; FAB-MS, MH.sup.+ 940.9, MNa.sup.+ 963.3. 
EXAMPLE 19 
Ac-D-Dip-Leu-Asp-Glu-Ile-Trp; FAB-MS, MH.sup.+ 938.2. 
EXAMPLE 20 
Ac-D-Dip-Glu-Asp-Ile-Ile-Trp; FAB-MS, MH.sup.+ 940.5. 
EXAMPLE 21 
Ac-D-Dip-Orn-Asp-Ile-Ile-Trp; FAB-MS, MH.sup.+ 925.1. 
EXAMPLE 22 
Ac-D-Dip-Leu-Asp(NMe)-Ile-Ile-Trp; FAB-MS, MNa.sup.+ 960.7. 
EXAMPLE 23 
Ac-D-Dip-D-Leu-Asp-Ile-Ile-Trp; FAB-MS, MH.sup.+ 924.12, M.sup.+ Na 946.0. 
EXAMPLE 24 
Disodium salt of Ac-D-Dip-Leu-Asp-Ile-Ile-Trp 
A saturated solution of sodium bicarbonate in water is prepared, diluted 
with water (1:10), chilled to 0.degree. C., and 10 mL of the solution is 
added to approximately 50 mg of Ac-D-Dip-Leu-Asp-Ile-Ile-Trp (Example 16) 
with stirring. The pH of the solution is greater than 9. After 10 minutes, 
the solution is passed through a C18 cartridge, washed with water (100 
mL), and the absorbed peptide is eluted with methanol (50 mL), 
concentrated under reduced pressure, resuspended in water (50 mL), and 
lyophilized (three times) to give the title compound. 
Ac-D-Dip-Leu-Asp-Ile-Ile-Trp; FAB-MS, MH.sup.+ 924.6, MNa.sup.+ 946.6, 
M2Na.sup.+ 968.6.