Design and development of a series of borocycles as selective, covalent kallikrein 5 inhibitors

Bioorg Med Chem Lett. 2019 Oct 15;29(20):126675. doi: 10.1016/j.bmcl.2019.126675. Epub 2019 Sep 7.

Abstract

The connection between Netherton syndrome and overactivation of epidermal/dermal proteases, particularly Kallikrein 5 (KLK5) has been well established and it is expected that a KLK5 inhibitor would improve the dermal barrier and also reduce the pain and itch that afflict Netherton syndrome patients. One of the challenges of covalent protease inhibitors has been achieving selectivity over closely related targets. In this paper we describe the use of structural insight to design and develop a selective and highly potent reversibly covalent KLK5 inhibitor from an initial weakly binding fragment.

Keywords: KLK1; KLK5; KLKB1; LEKTI; Netherton syndrome; SPINK5.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Benzamidines / chemistry*
  • Benzamidines / pharmacology
  • Binding Sites
  • Drug Evaluation, Preclinical
  • Humans
  • Isomerism
  • Kallikreins / antagonists & inhibitors*
  • Models, Molecular
  • Molecular Structure
  • Mutation
  • Netherton Syndrome / drug therapy*
  • Protein Binding
  • Serine Peptidase Inhibitor Kazal-Type 5 / genetics
  • Serine Proteinase Inhibitors / chemistry*
  • Serine Proteinase Inhibitors / pharmacology
  • Structure-Activity Relationship

Substances

  • Benzamidines
  • Serine Peptidase Inhibitor Kazal-Type 5
  • Serine Proteinase Inhibitors
  • KLK5 protein, human
  • Kallikreins
  • benzamidine