MOLECULAR MODELING AND QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP STUDIES IN PURSUIT OF HIGHLY POTENT SUBSTITUTED OCTANOAMIDE ANGIOTENSIN-II RECEPTOR ANTAGONISTS
COMPUTER-AIDED MOLECULAR DESIGN: APPLICATIONS IN AGROCHEMICALS, MATERIALS, AND PHARMACEUTICALS(1995)
Abstract
Findings from computational studies on novel nonpeptide angiotensin II (AT(1)) receptor antagonists were confirmed experimentally. To discover novel antihypertensives, several series of substituted 4-phenoxyprolyloctanoamides containing an imidazole ring were derived from substituted 4-amino-N-imidazolyl-2-octanoic acids previously disclosed by our laboratories. The title compounds interact with the AT(1) receptor in a highly stereospecific manner and define a subsite of the receptor not accessed by losartan, a well-known nonpeptide AT(1) antagonist. Molecular modeling correctly predicted the more active enantiomer of the N-imidazolyl-2-octanoic acids. A quadratic relationship between binding affinity and computed octanol/water partition coefficient for the para substituted phenoxy derivatives was found. Optimal in vivo pharmacology was achieved with triacids LY301875 (p-CH2COOH, pK(B) = 9.6) and LY303336 (p-CH2PO3H2, pK(B) = 9.1), both of which are orally bioavailable.
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