Biphenylsulfonamide endothelin receptor antagonists. 4. Discovery of N-[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]- 2-yl]methyl]-N,3,3-trimethylbutanamide (BMS-207940), a highly potent and orally active ET(A) selective antagonist.
We have previously disclosed the selective ET(A) receptor antagonist N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide (1, BMS-193884) as a clinical development candidate. Additional SAR studies at the 2'-position of 1 led to the identification of several analogues with improved binding affinity as well as selectivity for the ET(A) receptor. Following the discovery that a 3-amino-isoxazole group displays significantly improved metabolic stability in comparison to its 5-regioisomer, the 3-amino-isoxazole group was combined with the optimal 2'-substituent leading to 16a (BMS-207940). Compound 16a is an extremely potent (ET(A) K(i) = 10 pM) and selective (80,000-fold for ET(A) vs ET(B)) antagonist. It is also 150-fold more potent and >6-fold more selective than 1. The bioavailability of 16a was 100% in rats and the systemic clearance and volume of distribution are higher than that of 1. In rats, intravenous 16a blocks big ET pressor responses with 30-fold greater potency than 1. After oral dosing at 3 micromol/kg, 16a displays enhanced duration relative to 1.
Murugesan
Natesan
N
Department of Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-5400, USA. murugesan@bms.com
Gu
Zhengxiang
Z
Spergel
Steven
S
Young
Marian
M
Chen
Ping
P
Mathur
Arvind
A
Leith
Leslie
L
Hermsmeier
Mark
M
Liu
Eddie C-K
EC
Zhang
Rongan
R
Bird
Eileen
E
Waldron
Tom
T
Marino
Anthony
A
Koplowitz
Barry
B
Humphreys
W Griffith
WG
Chong
Saeho
S
Morrison
Richard A
RA
Webb
Maria L
ML
Moreland
Suzanne
S
Trippodo
Nick
N
Barrish
Joel C
JC
D000284:Administration, Oral; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D016466:CHO Cells; D018938:Caco-2 Cells; D002339:Carotid Arteries / Q000187:drug effects / Q000502:physiology; D006224:Cricetinae; D065128:Endothelin Receptor Antagonists; D006801:Humans; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D010080:Oxazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
D065128:Endothelin Receptor Antagonists; D007555:Isoxazoles; C470655:N-((2'-(((4,5-dimethyl-3-isoxazolyl)amino)sulfonyl)-4-(2-oxazolyl)(1,1'-biphenyl)-2-yl)methyl)-N,3,3-trimethylbutanamide; D010080:Oxazoles; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013449:Sulfonamides