New renin inhibitors homologous with pepstatin

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Abstract
Four homologs of pepstatin, the potent but poorly soluble inhibitor of aspartic proteinases, were synthesized by coupling to the C-terminus of the natural pentapeptide the following amino acid residues: L-arginine methyl ester, L-aspartic acid, L-glutamic acid and the dipeptide L-aspartyl-L-arginine. The peptide-coupling reagent used, benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate, allowed readily pure pepstatin homologs with high yields (60-83%) to be obtained. Pepstatylarginine methyl ester and pepstatylglutamic acid were .apprx. 1 order of magnitude more water-soluble than pepstatin. The 4 homologs and pepstatin were tested in vitro as inhibitors for highly purified pig and human renins acting on the N-acetyltetradecapeptide substrate. The 50% inhibitory concentrations (IC50) of the homologs ranged from 0.01-1 .mu.M against porcine renin at pH 6.0 (pepstatin IC50 .apprx. 0.32 .mu.M) and from 5.8-41 .mu.M against human renin at pH 6.5 (pepstatin IC50 .apprx. 17 .mu.M). By 3 different graphical methods pepstatin and the 4 homologs behaved as competitive inhibitors for porcine renin. The most potent inhibitors were pepstatylaspartic acid and pepstatylglutamic acid, with inhibitory constants respectively 2- and 10-fold smaller than that of pepstatin. By coupling glutamic acid to pepstatin, the ratio solubility/inhibitory constant was increased by 2 orders of magnitude.