Document Detail

Discovery and SAR of 6-Alkyl-2,4-diaminopyrimidines as Histamine H4 Receptor Antagonists.
MedLine Citation:
PMID:  24495018     Owner:  NLM     Status:  Publisher    
This report discloses the discovery and SAR of a series of 6-alkyl-2-aminopyrimidine derived histamine H4 antagonists that led to the development of JNJ 39758979, which has been studied in phase 2 clinical trials in asthma and atopic dermatitis. Building on our SAR studies of saturated derivatives from the indole carboxamide series, typified by JNJ 7777120, and incorporating knowledge from the tricyclic pyrimidines led us to the 6-alkyl-2,4-diaminopyrimidine series. A focused medicinal chemistry effort delivered several 6-alkyl-2,4-diaminopyrimidines that behaved as antagonists at both the human and rodent H4 receptor. Further optimization led to a panel of antagonists that were profiled in animal models of inflammatory disease. Based on the preclinical profile and efficacy in several animal models, JNJ 39758979 was selected as a clinical candidate, however further development was halted during phase II due to the observation of drug induced agranulocytosis (DIAG) in two subjects.
Brad M Savall; Frank Chavez; Kevin Tays; Paul J Dunford; Jeffery Cowden; Michael David Hack; Ronald L Wolin; Robin L Thurmond; James Patrick Edwards
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-2-4
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  -     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2014 Feb 
Date Detail:
Created Date:  2014-2-5     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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