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

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...

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Bibliographic Details
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
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Summary:	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.
Bibliography:	http://dx.doi.org/10.1016/j.bmcl.2013.02.091 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2013.02.091