| Abstract
| - The ETA 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 AT1 receptorantagonists, including irbesartan (3). Thus, it was hypothesized that merging the structuralelements of 2 with those of the biphenyl AT1 antagonists (e.g., irbesartan) would yield acompound with dual activity for both receptors. This strategy led to the design, synthesis, anddiscovery of (15) (4‘-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-N-(3,4-dimethyl-5-isoxazolyl)-2‘-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl]-[1,1‘-biphenyl]-2-sulfonamide, BMS-248360) as a potent and orally active dual antagonist of both AT1 and ETA receptors. Compound15 represents a new approach to treating hypertension.
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