Synthesis and optimization of novel (3S,5R)-5-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)piperidine-3-carboxamides as orally active renin inhibitors

被引：9

作者：

Mori, Yutaka ^{[1
]}

Ogawa, Yasuyuki ^{[2
]}

Mochizuki, Akiyoshi ^{[3
]}

Nakamura, Yuji ^{[3
]}

Fujimoto, Teppei ^{[3
]}

Sugita, Chie ^{[3
]}

Miyazaki, Shojiro ^{[3
]}

Tamaki, Kazuhiko ^{[3
]}

Nagayama, Takahiro ^{[4
]}

Nagai, Yoko ^{[5
]}

Inoue, Shin-ichi ^{[5
]}

Chiba, Katsuyoshi ^{[6
]}

Nishi, Takahide ^{[7
]}

机构：

[1] Daiichi Sankyo Co Ltd, New Modal Res Labs, Shinagawa Ku, Tokyo 1408710, Japan

[2] Daiichi Sankyo Co Ltd, Venture Sci Labs, Shinagawa Ku, Tokyo 1408710, Japan

[3] Daiichi Sankyo Co Ltd, Med Chem Res Labs, Shinagawa Ku, Tokyo 1408710, Japan

[4] Daiichi Sankyo Co Ltd, Cardiovasc Metabol Res Labs, Shinagawa Ku, Tokyo 1408710, Japan

[5] Daiichi Sankyo Co Ltd, Drug Metab & Pharmacokinet Res Labs, Shinagawa Ku, Tokyo 1408710, Japan

[6] Daiichi Sankyo Co Ltd, Med Safety Res Labs, Edogawa Ku, Tokyo 1348630, Japan

[7] Daiichi Sankyo India Pharma Pvt Ltd, Daiichi Sankyo Life Sci Res Ctr India, Gurgaon 122015, Haryana, India

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2013年 / 21卷 / 18期

关键词：

Hypertension; Renin; Piperidine; Ketopiperazine; TRANSGENIC RATS; BLOOD-PRESSURE; DISCOVERY; DESIGN; ALISKIREN; POTENT; MARMOSETS; DS-8108B;

D O I：

10.1016/j.bmc.2013.06.057

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

We report synthesis and optimization of a series of (3S,5R)-5-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)piperidine-3-carboxamides as renin inhibitors. Chemical modification of P-1', P-2' and P-3 portions led to a promising 3,5-disubstituted piperidine 32o showing high renin inhibitory activity and favorable oral exposure in both rats and cynomolgus monkeys with acceptable CYP and hERG current inhibition. Compound 32o exhibited a significant blood pressure lowering effect by oral administration in two hypertensive animal models, double transgenic rats and furosemide pretreated cynomolgus monkeys. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：5907 / 5922

页数：16

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