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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 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.

SUBMITTER: Imaeda Y

PROVIDER: S-EPMC5066151 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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

Imaeda Yasuhiro Y Tokuhara Hidekazu H Fukase Yoshiyuki Y Kanagawa Ray R Kajimoto Yumiko Y Kusumoto Keiji K Kondo Mitsuyo M Snell Gyorgy G Behnke Craig A CA Kuroita Takanobu T

ACS medicinal chemistry letters 20160912 10

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)carbonyl ...[more]

PMID: 27774132

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