Discovery and SAR of 6-Alkyl-2,4-diaminopyrimidines as Histamine H4 Receptor Antagonists

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• 作者：Brad M. Savall ; Frank Chavez ; Kevin Tays ; Paul J. Dunford ; Jeffery M. Cowden ; Michael D. Hack ; Ronald L. Wolin ; Robin L. Thurmond ; James P. Edwards
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：March 27, 2014
• 年：2014
• 卷：57
• 期：6
• 页码：2429-2439
• 全文大小：554K
• 年卷期：v.57,no.6(March 27, 2014)
• ISSN：1520-4804

文摘

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 II 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. On the basis of 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 because of the observation of drug-induced agranulocytosis (DIAG) in two subjects.