title: 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.
abstract: 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.
authors.affiliation: New Modality Research Laboratories, Daiichi Sankyo Co., Ltd, Shinagawa-ku, Tokyo, Japan. mori.yutaka.c7@daiichisankyo.co.jp
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Mori
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Ogawa
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Mochizuki
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Teppei
authors.initials: T
authors.lastname: Fujimoto
authors.forename: Chie
authors.initials: C
authors.lastname: Sugita
authors.forename: Shojiro
authors.initials: S
authors.lastname: Miyazaki
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Tamaki
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nagayama
authors.forename: Yoko
authors.initials: Y
authors.lastname: Nagai
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Inoue
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Chiba
authors.forename: Takahide
authors.initials: T
authors.lastname: Nishi
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D005665:Furosemide / Q000494:pharmacology; D006207:Half-Life; D006973:Hypertension / Q000188:drug therapy; D008252:Macaca fascicularis; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D055647:Rats, Transgenic; D012083:Renin / Q000378:metabolism; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D005665:Furosemide; D010879:Piperazines; D010880:Piperidines; D011480:Protease Inhibitors; D012083:Renin; D000092502:Renin Inhibitors; C587295:(3S,5R)-5-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)piperidine-3-carboxamide; C032727:piperidine
keywords: Hypertension; Ketopiperazine; Piperidine; Renin