Discovery of TAK-272: A Novel, Potent, and Orally Active Renin Inhibitor

Abstract

The aspartic proteinase renin is an attractive target for the treatment of hypertension and cardiovascular/renal disease such as chronic kidney disease and heart failure. We introduced an S1' site binder into the lead compound <b>1</b> guided by structure-based drug design (SBDD), and further optimization of physicochemical properties led to the discovery of benzimidazole derivative <b>10</b> (1-(4-methoxybutyl)-<i>N</i>-(2-methylpropyl)-<i>N</i>-[(3<i>S</i>,5<i>R</i>)-5-(morpholin-4-yl)carbonylpiperidin-3-yl]-1<i>H-</i>benzimidazole-2-carboxamide hydrochloride, TAK-272) as a highly potent and orally active renin inhibitor. Compound <b>10</b> demonstrated good oral bioavailability (BA) and long-lasting efficacy in rats. Compound <b>10</b> is currently in clinical trials.