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
收藏
页码：933 / 938
页数：6
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