The identification of 4,7-disubstituted naphthoic acid derivatives as UDP-competitive antagonists of P2Y14

Bioorg Med Chem Lett. 2011 May 15;21(10):2836-9. doi: 10.1016/j.bmcl.2011.03.081. Epub 2011 Mar 31.

Abstract

A weak, UDP-competitive antagonist of the pyrimidinergic receptor P2RY(14) with a naphthoic acid core was identified through high-throughput screening. Optimization provided compounds with improved potency but poor pharmacokinetics. Acylglucuronidation was determined to be the major route of metabolism. Increasing the electron-withdrawing nature of the substituents markedly reduced glucuronidation and improved the pharmacokinetic profile. Additional optimization led to the identification of compound 38 which is an 8 nM UDP-competitive antagonist of P2Y(14) with a good pharmacokinetic profile.

MeSH terms

  • Animals
  • Binding, Competitive
  • Carboxylic Acids / chemical synthesis*
  • Carboxylic Acids / chemistry
  • Carboxylic Acids / pharmacokinetics
  • Carboxylic Acids / pharmacology
  • Mice
  • Molecular Structure
  • Naphthalenes / chemical synthesis*
  • Naphthalenes / chemistry
  • Naphthalenes / pharmacokinetics
  • Naphthalenes / pharmacology
  • Pan troglodytes
  • Protein Binding / drug effects
  • Purinergic P2 Receptor Antagonists / chemical synthesis*
  • Purinergic P2 Receptor Antagonists / chemistry
  • Purinergic P2 Receptor Antagonists / pharmacokinetics
  • Purinergic P2 Receptor Antagonists / pharmacology
  • Receptors, Purinergic P2*
  • Receptors, Purinergic P2Y
  • Structure-Activity Relationship
  • Uridine Diphosphate*

Substances

  • Carboxylic Acids
  • Naphthalenes
  • P2ry14 protein, mouse
  • Purinergic P2 Receptor Antagonists
  • Receptors, Purinergic P2
  • Receptors, Purinergic P2Y
  • 1-naphthoic acid
  • Uridine Diphosphate