Discovery and structure-activity relationship study of 1,3,6-trisubstituted 1,4-diazepane-7-ones as novel human kallikrein 7 inhibitors

Bioorg Med Chem Lett. 2017 Dec 1;27(23):5272-5276. doi: 10.1016/j.bmcl.2017.10.030. Epub 2017 Oct 17.

Abstract

Compound 1, composed of a 1,3,6-trisubstituted 1,4-diazepane-7-one, was discovered as a novel human kallikrein 7 (KLK7, stratum corneum chymotryptic enzyme, SCCE) inhibitor, and its derivatives were synthesized and evaluated. Structure-activity relationship studies of the amidoxime unit and benzoic acid part of this new scaffold led to the identification of 25 and 34, which were more potent than the hit compound, 1. The X-ray co-crystal structure of compound 25 and human KLK7 revealed the characteristic interactions and enabled explanations of the structure-activity relationship.

Keywords: 1,4-Diazepane-7-one; Inhibitor; KLK7; SCCE; X-ray co-crystal.

MeSH terms

  • Azepines / chemical synthesis
  • Azepines / chemistry
  • Azepines / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Kallikreins / antagonists & inhibitors*
  • Kallikreins / metabolism
  • Molecular Structure
  • Serine Proteinase Inhibitors / chemical synthesis
  • Serine Proteinase Inhibitors / chemistry
  • Serine Proteinase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Azepines
  • Serine Proteinase Inhibitors
  • KLK7 protein, human
  • Kallikreins