Discovery of a Series of Pyrimidine Carboxamides as Inhibitors of Vanin-1

J Med Chem. 2022 Jan 13;65(1):757-784. doi: 10.1021/acs.jmedchem.1c01849. Epub 2021 Dec 30.


A diaryl ketone series was identified as vanin-1 inhibitors from a high-throughput screening campaign. While this novel scaffold provided valuable probe 2 that was used to build target confidence, concerns over the ketone moiety led to the replacement of this group. The successful replacement of this moiety was achieved with pyrimidine carboxamides derived from cyclic secondary amines that were extensively characterized using biophysical and crystallographic methods as competitive inhibitors of vanin-1. Through optimization of potency and physicochemical and ADME properties, and guided by co-crystal structures with vanin-1, 3 was identified with a suitable profile for advancement into preclinical development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidohydrolases / antagonists & inhibitors*
  • Animals
  • Colitis / chemically induced
  • Colitis / drug therapy
  • Crystallography, X-Ray
  • Dextran Sulfate
  • Dogs
  • Drug Discovery
  • Female
  • GPI-Linked Proteins / antagonists & inhibitors
  • High-Throughput Screening Assays
  • Ketones / chemistry
  • Mice
  • Mice, Inbred BALB C
  • Models, Molecular
  • Pyridines / chemical synthesis*
  • Pyridines / pharmacokinetics
  • Pyridines / pharmacology*
  • Rats
  • Structure-Activity Relationship


  • GPI-Linked Proteins
  • Ketones
  • Pyridines
  • Dextran Sulfate
  • Amidohydrolases
  • pantetheinase