Diaminopyrimidines, diaminopyridines and diaminopyridazines as histamine H4 receptor modulators

Histamine H4 receptor antagonists. [Display omitted] Previously disclosed H4 receptor modulators, the triamino substituted pyridines and pyrimidines, contain a free primary amino (–NH2) group. In this Letter we demonstrate that an exocyclic amine (NH2) is not needed to maintain affinity, and also sh...

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Published inBioorganic & medicinal chemistry letters Vol. 25; no. 4; pp. 956 - 959
Main Authors Savall, Brad M., Meduna, Steven P., Tays, Kevin, Cai, Hui, Thurmond, Robin L., McGovern, Patricia, Gaul, Michael, Zhao, Bao-Ping, Edwards, James P.
Format Journal Article
LanguageEnglish
Published England Elsevier Ltd 15.02.2015
Subjects
Antagonists
Histamine H4
Humans
Pyridazine
Pyridine
Pyridines - chemistry
Pyridines - pharmacology
Pyrimidine
Receptors, G-Protein-Coupled - drug effects
Receptors, Histamine - drug effects
Receptors, Histamine H4
Antagonists
Pyridine
Histamine H4
Pyridazine
Pyrimidine
Histamine H
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Summary:Histamine H4 receptor antagonists. [Display omitted] Previously disclosed H4 receptor modulators, the triamino substituted pyridines and pyrimidines, contain a free primary amino (–NH2) group. In this Letter we demonstrate that an exocyclic amine (NH2) is not needed to maintain affinity, and also show a significant divergence in the SAR of the pendant diamine component. These des-NH2 azacycles also show a distinct functional spectrum, that appears to be influenced by the diamine component; in the case of the 1,3-amino pyrimidines, the preferred diamine is the amino pyrrolidine instead of the more common piperazines. Finally, we introduce 3,5-diamino pyridazines as novel histamine H4 antagonists.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2014.12.027