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

Yuji Nakamura; Chie Sugita; Masaki Meguro; Shojiro Miyazaki; Kazuhiko Tamaki; Mizuki Takahashi; Yoko Nagai; Takahiro Nagayama; Mikio Kato; Hiroshi Suemune; Takahide Nishi

doi:10.1016/j.bmcl.2012.05.092

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

Bioorg Med Chem Lett. 2012 Jul 15;22(14):4561-6. doi: 10.1016/j.bmcl.2012.05.092. Epub 2012 Jun 4.

Authors

Yuji Nakamura¹, Chie Sugita, Masaki Meguro, Shojiro Miyazaki, Kazuhiko Tamaki, Mizuki Takahashi, Yoko Nagai, Takahiro Nagayama, Mikio Kato, Hiroshi Suemune, Takahide Nishi

Affiliation

¹ Lead Discovery & Optimization Research Laboratories I, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.

PMID: 22726934
DOI: 10.1016/j.bmcl.2012.05.092

Abstract

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.

MeSH terms

Amides / chemistry*
Amides / pharmacology
Amination
Drug Design
Hydroxylation
Methylation
Models, Molecular
Piperazine
Piperazines / chemistry*
Renin / antagonists & inhibitors*
Structure-Activity Relationship

Substances

Amides
Piperazines
Piperazine
Renin