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

• Published in: Journal of medicinal chemistry Vol. 57; no. 6; pp. 2429 - 2439
• Main Authors: Savall, Brad M, Chavez, Frank, Tays, Kevin, Dunford, Paul J, Cowden, Jeffery M, Hack, Michael D, Wolin, Ronald L, Thurmond, Robin L, Edwards, James P
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 27.03.2014
• Subjects: Animals; Arthritis - chemically induced; Arthritis - prevention & control; Collagen; Dogs; Drug Design; Drug Discovery; Histamine; Histamine Antagonists - chemical synthesis; Histamine Antagonists - pharmacology; Indicators and Reagents; Lipopolysaccharides - pharmacology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Models, Molecular; Pruritus - chemically induced; Pruritus - prevention & control; Pyrimidines - chemical synthesis; Pyrimidines - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled - antagonists & inhibitors; Receptors, Histamine; Receptors, Histamine H4; Structure-Activity Relationship; Tumor Necrosis Factor-alpha - biosynthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm401727m

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.