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

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 H 4 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 H 4 R 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.