ABSTRACT
We prepared a new series of renin inhibitors based on dipeptide glycols, replacing the P4-P3 subsites with an O-(N-morpholinocarbonyl)-3-L-phenyllactic acid residue. This modification proved bioisosteric with Boc-L-phenylalanine, giving rise to highly potent human renin inhibitors (1-5 nM), e.g., SC-46944 (IC50 = 5 nM). Moreover, this change produced compounds that are orally efficacious in reducing plasma renin activity in salt-depleted marmosets.
Subject(s)
Dipeptides/pharmacology , Glycols/pharmacology , Lactates , Morpholines , Renin/antagonists & inhibitors , Animals , Callitrichinae , Dipeptides/chemical synthesis , Glycols/chemical synthesis , Humans , Molecular Conformation , Molecular Structure , Morpholines/pharmacology , Renin/bloodABSTRACT
We prepared a series of novel dipeptide amides of the formula Boc-Phe-Leu-X, where X is a 3-amino-3-alkyl-1,2-propanediol with lower alkyl substitutions at C-1, in order to probe accessory binding sites in the enzyme renin. This approach was successful in generating potent inhibitors of human and hog renin in vitro. Moreover, these inhibitors were able to effect in vivo reduction of plasma renin activity (PRA) in the conscious salt-depleted rhesus monkey (i.v. route); this effect was related to the size of the C-1 alkyl group.
