Discovery of N-isoxazolyl biphenylsulfonamides as potent dual angiotensin II and endothelin A receptor antagonists.

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Murugesan N, Tellew JE, Gu Z, Kunst BL, Fadnis L, Cornelius LA, Baska RA, Yang Y, Beyer SM, Monshizadegan H, Dickinson KE, Panchal B, Valentine MT, Chong S, Morrison RA, Carlson KE, Powell JR, Moreland S, Barrish JC, Kowala MC, Macor JE

Discovery of N-isoxazolyl biphenylsulfonamides as potent dual angiotensin II and endothelin A receptor antagonists.

J Med Chem. 2002 Aug 29;45(18):3829-35.

PubMed ID

12190306 [ View in PubMed

]

Abstract

The ET(A) receptor antagonist (2) (N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-[1,1'-biphenyl]-2-sulfonamide, BMS-193884) shares the same biphenyl core as a large number of AT(1) receptor antagonists, including irbesartan (3). Thus, it was hypothesized that merging the structural elements of 2 with those of the biphenyl AT(1) antagonists (e.g., irbesartan) would yield a compound with dual activity for both receptors. This strategy led to the design, synthesis, and discovery of (15) (4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-N-(3,4-dimethyl-5-is oxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl]-[1,1'-biphenyl]-2-sulfon amide, BMS-248360) as a potent and orally active dual antagonist of both AT(1) and ET(A) receptors. Compound 15 represents a new approach to treating hypertension.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Irbesartan	Type-1 angiotensin II receptor	Ki (nM)	1.1	N/A	N/A	Details