A novel series of histamine H4 receptor antagonists based on the pyrido[3,2-d]pyrimidine scaffold: comparison of hERG binding and target residence time with PF-3893787

Bioorg Med Chem Lett. 2013 May 1;23(9):2663-70. doi: 10.1016/j.bmcl.2013.02.091. Epub 2013 Mar 1.

Abstract

In this work we describe the optimization of a lead compound based on the quinazoline template to give a new series of potent pyrido[3,2-d]pyrimidines as histamine H4 receptor antagonists. The pyrido[3,2-d]pyrimidine ligands have significantly reduced hERG binding compared to clinical stage compound PF-3893787 while showing good affinities at the human and rodent histamine receptors. The receptor residence time of several of these new compounds was determined for the human H4R and compared with JNJ7777120 and PF-3893787. The pyrido[3,2-d]pyrimidines showed residence times lower than JNJ7777120 but comparable to the residence time of PF-3893787. Overall, the pyrido[3,2-d]pyrimidines show an excellent in vitro profile that warrants their further investigation in relevant models of human disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels / chemistry
  • Ether-A-Go-Go Potassium Channels / metabolism*
  • Half-Life
  • Histamine Antagonists / chemical synthesis
  • Histamine Antagonists / chemistry*
  • Histamine Antagonists / pharmacokinetics
  • Humans
  • Indoles / chemistry
  • Indoles / pharmacokinetics
  • Kinetics
  • Mice
  • Piperazines / chemistry
  • Piperazines / pharmacokinetics
  • Protein Binding
  • Pyridines / chemical synthesis
  • Pyridines / chemistry*
  • Pyridines / pharmacokinetics
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacokinetics
  • Pyrrolidines / chemistry*
  • Pyrrolidines / pharmacokinetics
  • Rats
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Histamine / metabolism
  • Receptors, Histamine H4
  • Structure-Activity Relationship

Substances

  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels
  • HRH4 protein, human
  • Histamine Antagonists
  • Indoles
  • KCNH2 protein, human
  • Piperazines
  • Pyridines
  • Pyrimidines
  • Pyrrolidines
  • Receptors, G-Protein-Coupled
  • Receptors, Histamine
  • Receptors, Histamine H4
  • pyrido(3,2-d)pyrimidine
  • 1-((5-chloro-1H-indol-2-yl)carbonyl)-4-methylpiperazine
  • PF-3893787