SYNTHESIS AND BIOLOGICAL-ACTIVITY OF POTENT, LOW-MOLECULAR-WEIGHT RENIN INHIBITORS

A series of renin inhibitors containing the dipeptide transition state mimics (2R,4S,5S)-5-amino-4-hydroxy-2- methyl-6-cyclohexyl hexanoic a cid (Cha-Psi[CH(OH)CH2]Ala) and ,4S,5S)-5-amino-3-hydroxy-2-isopropyl- 6-cyclohexyl hexanoic acid (Cha-Psi[CH(OH)CH2]Val) were prepared. A st ructure-activity study, using pseudopeptide (Boc-Phe-His-Leu-Psi[CH(OH )CH2]Val-Ile-His-OH) as our lead structure, led to a new series of inh ibitors, which correspond to tripeptides and contain no natural amino acids. For example, R,S-Bpma-Ape-Cha-Psi[CH(OH)CH2]Ala-NH2 (IC50 = 1.2 6 nM against human plasma renin at pH 6.0; molecular weight = 564) has only two thirds of the molecular weight but twice the potency of our original lead. This new class of low molecular weight renin inhibitor displays excellent specificity toward human renin versus the related a spartic proteinase pepsin and angiotensin-l-converting enzyme. Example s are given of selected inhibitors showing encouraging evidence for in testinal absorption after intracolonic and oral administration in male Sprague-Dawley rats. (C) Munksgaard 1997.