Structure-based drug design of 1,3,6-trisubstituted 1,4-diazepan-7-ones as selective human kallikrein 7 inhibitors

Bioorg Med Chem Lett. 2018 May 1;28(8):1371-1375. doi: 10.1016/j.bmcl.2018.03.011. Epub 2018 Mar 3.

Abstract

A novel series of 1,3,6-trisubstituted 1,4-diazepan-7-ones were investigated as human kallikrein 7 (KLK7, stratum corneum chymotryptic enzyme) inhibitors. Based on the X-ray co-crystal structure of compound 1 bound to human KLK7, the derivatives of this scaffold were designed, synthesized, and evaluated. Through structure-activity relationship studies focused on the side chain located in the prime site region of the enzyme, representative compounds 15, 33a, and 35a were identified as highly potent and selective inhibitors of human KLK7.

Keywords: 1,4-Diazepan-7-one; Atopic dermatitis; Kallikrein 7 inhibitor; Serine protease; Structure-based drug design.

MeSH terms

  • Azepines / chemical synthesis
  • Azepines / chemistry
  • Azepines / pharmacology*
  • Binding Sites
  • Crystallography, X-Ray
  • Drug Design
  • Humans
  • Kallikreins / antagonists & inhibitors*
  • Kallikreins / chemistry
  • Molecular Docking Simulation
  • Molecular Structure
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Azepines
  • KLK7 protein, human
  • Kallikreins