Biphenylsulfonamide endothelin receptor antagonists. 2. Discovery of 4'-oxazolyl biphenylsulfonamides as a new class of potent, highly selective ET(A) antagonists.
The synthesis and structure-activity relationship (SAR) studies of a series of 4'-oxazolyl-N-(3,4-dimethyl-5-isoxazolyl)[1, 1'-biphenyl]-2-sulfonamide derivatives as endothelin-A (ET(A)) receptor antagonists are described. The data reveal a remarkable improvement in potency and metabolic stability when the 4'-position of the biphenylsulfonamide is substituted with an oxazole ring. Additional 2'-substitution of an acylaminomethyl group further increased the binding activity and provided one of the first subnanomolar ET(A)-selective antagonists in the biphenylsulfonamide series (17, ET(A) K(i) = 0.2 nM). Among the compounds described, 3 (N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1, 1'-biphenyl]-2-sulfonamide; BMS-193884) had the optimum pharmacological profile and was therefore selected as a clinical candidate for studies in congestive heart failure.
Murugesan
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Department of Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-5400, USA. murugesan@bms.com
Gu
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Stein
P D
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Spergel
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S
Mathur
A
A
Leith
L
L
Liu
E C
EC
Zhang
R
R
Bird
E
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Waldron
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T
Marino
A
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Morrison
R A
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Webb
M L
ML
Moreland
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Barrish
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JC
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D002339:Carotid Arteries / Q000187:drug effects / Q000502:physiology; D004353:Drug Evaluation, Preclinical; D065128:Endothelin Receptor Antagonists; D006973:Hypertension / Q000503:physiopathology; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D009119:Muscle Contraction; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D044022:Receptor, Endothelin A; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C412823:BMS 193884; D065128:Endothelin Receptor Antagonists; D010080:Oxazoles; D044022:Receptor, Endothelin A; D013449:Sulfonamides