Discovery of non-peptidic P 2–P 3 butanediamide renin inhibitors with high oral efficacy

B Simoneau, P Lavallée, PC Anderson, M Bailey…

Index: Simoneau, Bruno; Lavallee, Pierre; Anderson, Paul C.; Bailey, Murray; Bantle, Gary; Berthiaume, Sylvie; Chabot, Catherine; Fazal, Gulrez; Halmos, Ted; Ogilvie, William W.; Poupart, Marc-Andre; Thavonekham, Bounkham; Xin, Zhili; Thibeault, Diane; Boelger, Gordon; Panzenbeck, Maret; Winquist, Raymond; Jung, Grace L. Bioorganic and Medicinal Chemistry, 1999 , vol. 7, # 3 p. 489 - 508

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Citation Number: 38

Abstract

A new series of non-peptidic renin inhibitors having a 2-substituted butanediamide moiety at the P2 and P3 positions has been identified. The optimized inhibitors have IC50 values of 0.8 to 1.4 nM and 2.5 to 7.6 nM in plasma renin assays at pH 6.0 and 7.4, respectively. When evaluated in the normotensive cynomolgus monkey model, two of the most potent inhibitors were orally active at a dose as low as 3mg/kg. These potent renin inhibitors are ...