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

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 9; pp. 2663 - 2670
• Main Authors: Andaloussi, Mounir, Lim, Herman D., van der Meer, Tiffany, Sijm, Maarten, Poulie, Chris B.M., de Esch, Iwan J.P., Leurs, Rob, Smits, Rogier A.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.05.2013
• Subjects: Animals; antagonists; Cell Line; chemistry; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels - chemistry; Ether-A-Go-Go Potassium Channels - metabolism; GPCR; Half-Life; hERG; histamine; Histamine Antagonists - chemical synthesis; Histamine Antagonists - chemistry; Histamine Antagonists - pharmacokinetics; Histamine H4 receptor; human diseases; Humans; Indoles - chemistry; Indoles - pharmacokinetics; Kinetics; Mice; PF-3893787; Piperazines - chemistry; Piperazines - pharmacokinetics; Protein Binding; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacokinetics; Pyrido[3,2-d]pyrimidine; pyrimidines; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacokinetics; Pyrrolidines - chemistry; Pyrrolidines - pharmacokinetics; Rats; receptors; Receptors, G-Protein-Coupled - antagonists & inhibitors; Receptors, G-Protein-Coupled - metabolism; Receptors, Histamine - metabolism; Receptors, Histamine H4; Residence time; rodents; Structure-Activity Relationship; GPCR; hERG; Residence time; Histamine H4 receptor; Pyrido[3,2-d]pyrimidine; PF-3893787
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.02.091

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.