Discovery of novel series of 6-benzyl substituted 4-aminocarbonyl-1,4-diazepane-2,5-diones as human chymase inhibitors using structure-based drug design

Taisaku Tanaka; Hajime Sugawara; Hiroshi Maruoka; Seiichi Imajo; Tsuyoshi Muto

doi:10.1016/j.bmc.2013.04.079

Discovery of novel series of 6-benzyl substituted 4-aminocarbonyl-1,4-diazepane-2,5-diones as human chymase inhibitors using structure-based drug design

Bioorg Med Chem. 2013 Jul 15;21(14):4233-49. doi: 10.1016/j.bmc.2013.04.079. Epub 2013 May 9.

Authors

Taisaku Tanaka¹, Hajime Sugawara, Hiroshi Maruoka, Seiichi Imajo, Tsuyoshi Muto

Affiliation

¹ Asubio Pharma Co., Ltd, 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan. tanaka.taisaku.fu@asubio.co.jp

PMID: 23719288
DOI: 10.1016/j.bmc.2013.04.079

Abstract

A novel series of 6-benzyl substituted 4-aminocarbonyl-1,4-diazepane-2,5-diones were explored as human chymase inhibitors using structure-based drug design according to the X-ray cocrystal structure of chymase and compound 1. The optimization focused on the prime site led to the attainment of compounds that showed potent inhibitory activity, and among them, 18R shows a novel interaction mode.

MeSH terms

Azepines / chemical synthesis*
Azepines / chemistry
Azepines / pharmacology
Catalytic Domain
Chymases / antagonists & inhibitors*
Crystallography, X-Ray
Drug Design*
Enzyme Activation / drug effects
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology
Ethylmorphine / chemical synthesis*
Ethylmorphine / chemistry
Ethylmorphine / pharmacology
Humans
Inhibitory Concentration 50
Molecular Structure
Structure-Activity Relationship

Substances

1,4-diazepane
6-(5-chloro-2-methoxybenzyl)-4-alarkylaminocarbonyl-1,4-diazepane-2,5-dione
Azepines
Enzyme Inhibitors
Chymases
Ethylmorphine