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

被引：20

作者：

Imaeda, Yasuhiro ^{[1
]}

Tokuhara, Hidekazu ^{[1
]}

Fukase, Yoshiyuki ^{[1
]}

Kanagawa, Ray ^{[1
]}

Kajimoto, Yumiko ^{[1
]}

Kusumoto, Keiji ^{[1
]}

Kondo, Mitsuyo ^{[1
]}

Snell, Gyorgy ^{[2
]}

Behnke, Craig A. ^{[2
,3
]}

Kuroita, Takanobu ^{[1
]}

机构：

[1] Takeda Pharmaceut Co Ltd, Pharmaceut Res Div, 26-1 Muraoka Higashi 2 Chome, Fujisawa, Kanagawa 2518555, Japan

[2] Takeda Calif Inc, 10410 Sci Ctr Dr, San Diego, CA 92121 USA

[3] Sapphire Energy Inc, 9363 Towne Ctr Dr, San Diego, CA 92121 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2016年 / 7卷 / 10期

基金：

美国国家卫生研究院;

关键词：

Renin inhibitor; TAK-272; benzimidazole; hypertension; SBDD; dTg rat; HYPERTENSION; PIPERIDINES; EFFICIENCY; ALISKIREN; DESIGN; SYSTEM;

D O I：

10.1021/acsmedchemlett.6b00251

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：933 / 938

页数：6

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