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

High Resolution Image Download MS PowerPoint Slide 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 1 guided by structure-based drug design (SBDD), and further optimization of physicochemical properties led to the discovery of benzimidazole derivative 10 (1-(4-methoxybutyl)- N -(2-methylpropyl)- N -[(3 S,5 R )-5-(morpholin-4-yl)carbonylpiperidin-3-yl]-1 H- benzimidazole-2-carboxamide hydrochloride, TAK-272) as a highly potent and orally active renin inhibitor. Compound 10 demonstrated good oral bioavailability (BA) and long-lasting efficacy in rats. Compound 10 is currently in clinical trials.