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.

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Murugesan N, Gu Z, Spergel S, Young M, Chen P, Mathur A, Leith L, Hermsmeier M, Liu EC, Zhang R, Bird E, Waldron T, Marino A, Koplowitz B, Humphreys WG, Chong S, Morrison RA, Webb ML, Moreland S, Trippodo N, Barrish JC

J Med Chem. 2003 Jan 2;46(1):125-37.

PubMed ID

12502366 [ View in PubMed

]

Abstract

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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Bosentan	Endothelin B receptor	Ki (nM)	80	N/A	N/A	Details
Bosentan	Endothelin-1 receptor	Ki (nM)	8	N/A	N/A	Details