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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

2013; Elsevier BV; Volume: 21; Issue: 18 Linguagem: Inglês

10.1016/j.bmc.2013.06.057

1464-3391

Yutaka Mori, Yasuyuki Ogawa, Akiyoshi Mochizuki, Y. Nakamura, Teppei Fujimoto, Chie Sugita, Shojiro Miyazaki, Kazuhiko Tamaki, Takahiro Nagayama, Yoko Nagai, Shinichi Inoue, Katsuyoshi Chiba, Takahide Nishi,

Synthesis and Biological Evaluation

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 P1', P2' and P3 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.