Molecular Modeling and Quantitative Structure—Activity Relationship Studies in Pursuit of Highly Potent Substituted Octanoamide Angiotensin II Receptor Antagonists
Donald B. Boyd, Alan David Palkowitz, K. Jeff Thrasher, Kenneth L. Hauser, Celia A. Whitesitt, Jon K. Reel, Richard L. Simon, William Pfeifer, Sherryl L. Lifer, Kumiko Takeuchi, Vasu Vasudevan, Aaron D. Kossoy, Jack B. Deeter, Mitchell I. Steinberg, Karen M. Zimmerman, Sally A. Wiest, Winston S. Marshall · ACS symposium series · 1995
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 -CH 2 COOH, pK B = 9.6) and LY303336 ( P -CH 2 PO 3 H 2, pK B = 9.1), both of which are orally bioavailable.