Design and optimization of novel (2S,4S,5S)-5-amino-6-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)-4-hydroxy-2-isopropylhexanamides as renin inhibitors.
Introduction of the 2,2-dimethyl-4-phenylpiperazin-5-one scaffold into the P(3)-P(1) portion of the (2S,4S,5S)-5-amino-6-dialkylamino-4-hydroxy-2-isopropylhexanamide backbone dramatically increased the renin inhibitory activity without using the interaction to the S(3)(sp) pocket. Compound 31 exhibited >10,000-fold selectivity over other human proteases, and 18.5% oral bioavailability in monkey.
Lead Discovery & Optimization Research Laboratories I, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Yuji
Y
Nakamura
Chie
C
Sugita
Masaki
M
Meguro
Shojiro
S
Miyazaki
Kazuhiko
K
Tamaki
Mizuki
M
Takahashi
Yoko
Y
Nagai
Takahiro
T
Nagayama
Mikio
M
Kato
Hiroshi
H
Suemune
Takahide
T
Nishi
D000577:Amides / Q000737:chemistry* / Q000494:pharmacology; D000586:Amination; D015195:Drug Design; D006900:Hydroxylation; D008745:Methylation; D008958:Models, Molecular; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry*; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D000577:Amides; D000077489:Piperazine; D010879:Piperazines; D000092502:Renin Inhibitors