Identification of 3,6-disubstituted dihydropyrones as inhibitors of human lactate dehydrogenase

Bioorg Med Chem Lett. 2014 Dec 15;24(24):5683-5687. doi: 10.1016/j.bmcl.2014.10.067. Epub 2014 Oct 27.

Abstract

A series of 3,6-disubstituted dihydropyrones were identified as inhibitors of human lactate dehydrogenase (LDH)-A. Structure activity relationships were explored and a series of 6,6-spiro analogs led to improvements in LDHA potency (IC50 <350 nM). An X-ray crystal structure of an improved compound bound to human LDHA was obtained and it illustrated additional opportunities to enhance the potency of these compounds, resulting in the identification of 51 (IC50=30 nM).

Keywords: LDHA; Tumor metabolism; X-ray crystal structure.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Binding Sites
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • L-Lactate Dehydrogenase / antagonists & inhibitors*
  • L-Lactate Dehydrogenase / metabolism
  • Models, Molecular
  • Molecular Structure
  • Pyrones / chemical synthesis*
  • Pyrones / pharmacology*
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Pyrones
  • L-Lactate Dehydrogenase