Novel small renin inhibitors containing 4,5- or 3,5-dihydroxy-2-substituted-6-phenylhexanamide replacements at the P-2-P-3 sites

Renin inhibitors containing a 4,5- or a 3,5-dihydroxy-2-substituted-6-pheny lhexanamide fragment at the P-2- P-3 Sites have been prepared and evaluated . The four possible diastereomeric diols of the two series of inhibitors we re synthesized to determine the optimal configuration of the carbinol cente rs for these replacements. The most potent inhibitors of each series, 1a an d 2c have a molecular weight of only 503 and IC50 values of 23 and 20 nM in a human plasma renin assay at pH 6.0. Their very low aqueous solubility li mited their further evaluation. The efficacy of these P-2-P-3 replacements is a result of their ability to maintain the important hydrogen-bonds with the enzyme. Due to conformational differences with the dipeptide, adjustmen t at the P-2 Side chain was required. These 4,5- and 3,5-dihydroxyhexanamid e segments could be seen as novel N-terminal dipeptide replacements. (C) 19 98 Elsevier Science Ltd. All rights reserved.