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.

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