Discovery of non-peptidic P-2-P-3 butanediamide renin inhibitors with highoral efficacy

A new series of non-peptidic renin inhibitors having a 2-substituted butane diamide moiety at the P-2 and P-3 positions has been identified. The optimi zed inhibitors have IC50 values of 0.8 to 1.4 nM and 2.5 to 7.6 nM in plasm a renin assays at pH 6.0 and 7.4, respectively. When evaluated in the normo tensive cynomolgus monkey model, two of the most potent inhibitors were ora lly active at a dose as low as 3 mg/kg. These potent renin inhibitors are c haracterized by oral bioavailabilities of 40 and 89% in the cynomolgus monk ey. Inhibitor 3z (BILA 2157 BS) was selected as candidate for pre-developme nt. (C) 1999 Elsevier Science Ltd. All rights reserved.