LY-285434

A review with 79 referencesFindings from computational studies on novel nonpeptide angiotensin II (AT₁) receptor antagonists were confirmed exptl.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 the authors laboratoriesThe title compounds interact with the AT₁ receptor in a highly stereospecific manner and define a subsite of the receptor not accessed by losartan, a well-known nonpeptide AT₁ antagonist.Mol. modeling correctly predicted the more active enantiomer of the N-imidazolyl-2-octanoic acids.A quadratic relation between binding affinity and computed octanol/water partition coefficient for the para substituted phenoxy derivatives was found.Optimal in vivo pharmacol. 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.