Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 23, Issue 9, Pages 2663-2670Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2013.02.091
Keywords
Histamine H-4 receptor; GPCR; Pyrido[3,2-d]pyrimidine; hERG; Residence time; PF-3893787
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Funding
- COST action [BM0806]
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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 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. (C) 2013 Elsevier Ltd. All rights reserved.
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