Biphenylsulfonamide endothelin antagonists: structure-activity relationships of a series of mono- and disubstituted analogues and pharmacology of the orally active endothelin antagonist 2'-amino-N- (3,4-dimethyl-5-isoxazolyl)-4'-(2-methylpropyl)[1, 1'-biphenyl]-2-sulfonamide (BMS-187308).
Substitution at the ortho position of N-(3,4-dimethyl-5-isoxazolyl) benzenesulfonamide led to the identification of the biphenylsulfonamides as a novel series of endothelin-A (ETA) selective antagonists. Appropriate substitutions on the pendant phenyl ring led to improved binding as well as functional activity. A hydrophobic group such as isobutyl or isopropoxyl was found to be optimal at the 4'-position. Introduction of an amino group at the 2'-position also led to improved analogues. Combination of the optimal 4'-isobutyl substituent with the 2'-amino function afforded an analogue (20, BMS-187308) with improved ETA binding affinity and functional activity. Compound 20 also has good oral activity in inhibiting the pressor effect caused by an ET-1 infusion in rats. Doses of 10 and 30 micromol/kg iv 20 attenuated the pressor responses due to the administration of exogenous ET-1 to conscious monkeys, indicating that the compound inhibits the in vivo activity of endothelin-1 in nonhuman primates.
Murugesan
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Departments of Chemistry, Cardiovascular Agents, Cardiovascular Biochemistry, and Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA. Murugesan@bms.com
Gu
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Stein
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Bisaha
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Spergel
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Girotra
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Lee
V G
VG
Lloyd
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Misra
R N
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Schmidt
J
J
Mathur
A
A
Stratton
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L
Kelly
Y F
YF
Bird
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Waldron
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T
Liu
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EC
Zhang
R
R
Lee
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H
Serafino
R
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Abboa-Offei
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B
Mathers
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Giancarli
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Seymour
A A
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Webb
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Hunt
J T
JT
D000284:Administration, Oral; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D002339:Carotid Arteries / Q000187:drug effects / Q000502:physiology; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007555:Isoxazoles / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D044022:Receptor, Endothelin A; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D007555:Isoxazoles; D044022:Receptor, Endothelin A; D013449:Sulfonamides; C116543:BMS 187308