First insight into structure-activity relationships of selective meprin β inhibitors

Bioorg Med Chem Lett. 2017 Jun 1;27(11):2428-2431. doi: 10.1016/j.bmcl.2017.04.012. Epub 2017 Apr 5.

Abstract

The astacin proteases meprin α and β are emerging drug targets for treatment of disorders such as kidney failure, fibrosis or inflammatory bowel disease. However, there are only few inhibitors of both proteases reported to date. Starting from NNGH as lead structure, a detailed elaboration of the structure-activity relationship of meprin β inhibitors was performed, leading to compounds with activities in the lower nanomolar range. Considering the preference of meprin β for acidic residues in the P1' position, the compounds were optimized. Acidic modifications induced potent inhibition and >100-fold selectivity over other structurally related metalloproteases such as MMP-2 or ADAM10.

Keywords: Astacins; Hydroxamic acid; Meprin β; Sulfonamides.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Hydroxamic Acids / chemical synthesis
  • Hydroxamic Acids / chemistry*
  • Matrix Metalloproteinase Inhibitors / chemical synthesis
  • Matrix Metalloproteinase Inhibitors / chemistry
  • Metalloendopeptidases / antagonists & inhibitors*
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / chemistry*
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry*

Substances

  • Hydroxamic Acids
  • Matrix Metalloproteinase Inhibitors
  • N-isobutyl-N-(4-methoxyphenylsulfonyl)glycylhydroxamic acid
  • Protease Inhibitors
  • Sulfonamides
  • Metalloendopeptidases
  • meprin A