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

  • ACS Med Chem Lett. 2016 Sep 12;7(10):933-938. doi: 10.1021/acsmedchemlett.6b00251.
Yasuhiro Imaeda  1 ,  Hidekazu Tokuhara  1 ,  Yoshiyuki Fukase  1 ,  Ray Kanagawa  1 ,  Yumiko Kajimoto  1 ,  Keiji Kusumoto  1 ,  Mitsuyo Kondo  1 ,  Gyorgy Snell  2 ,  Craig A Behnke  2 ,  Takanobu Kuroita  1
Affiliations
  • 1. Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
  • 2. Takeda California, Inc. , 10410 Science Center Drive, San Diego, California 92121, United States.
PMID: 27774132 DOI: 10.1021/acsmedchemlett.6b00251
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 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-[(3S,5R)-5-(morpholin-4-yl)carbonylpiperidin-3-yl]-1H-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.

Keywords
Renin inhibitor; SBDD; TAK-272; benzimidazole; dTg rat; hypertension.
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