Further validation of strecker-type α-aminonitriles as a new class of potent human carbonic anhydrase II inhibitors: hit expansion within the public domain using differential scanning fluorimetry leads to chemotype refinement

J Enzyme Inhib Med Chem. 2020 Dec;35(1):165-171. doi: 10.1080/14756366.2019.1693556.

Abstract

Testing of an expanded, 800-compound set of analogues of the earlier described Strecker-type α-aminonitriles (selected from publicly available Enamine Ltd. Screening Collection) in thermal shift assay against bovine carbonic anhydrase (bCA) led to further validation of this new class of inhibitors and identification a new, refined chemotype represented by inhibitors with 10-improved potency. [Formula: see text].

Keywords: Differential scanning fluorimetry; carbonic anhydrase II; protein affinity; thermal shift assay.

MeSH terms

  • Animals
  • Carbonic Anhydrase II / antagonists & inhibitors*
  • Carbonic Anhydrase II / metabolism
  • Carbonic Anhydrase Inhibitors / chemical synthesis
  • Carbonic Anhydrase Inhibitors / chemistry
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Cattle
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Fluorometry
  • Humans
  • Molecular Structure
  • Nitriles / chemical synthesis
  • Nitriles / chemistry
  • Nitriles / pharmacology*
  • Structure-Activity Relationship

Substances

  • Carbonic Anhydrase Inhibitors
  • Nitriles
  • Carbonic Anhydrase II
  • CA2 protein, human

Grants and funding

This research was supported by the Russian Federation Government Megagrant 14.W03.031.0025.