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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
Authors:Mounir Andaloussi  Herman D. Lim  Tiffany van der Meer  Maarten Sijm  Chris B.M. Poulie  Iwan J.P. de Esch  Rob Leurs  Rogier A. Smits
Affiliation:1. Griffin Discoveries BV, Department of Medicinal Chemistry, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands;2. VU University Amsterdam, Department of Medicinal Chemistry, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands
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.
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