Discovery and SAR of 6-alkyl-2,4-diaminopyrimidines as histamine H₄ receptor antagonists.
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.
Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States.
Brad M
BM
Savall
Frank
F
Chavez
Kevin
K
Tays
Paul J
PJ
Dunford
Jeffery M
JM
Cowden
Michael D
MD
Hack
Ronald L
RL
Wolin
Robin L
RL
Thurmond
James P
JP
Edwards
D000818:Animals; D001168:Arthritis / Q000139:chemically induced / Q000517:prevention & control; D003094:Collagen; D004285:Dogs; D015195:Drug Design; D055808:Drug Discovery; D006632:Histamine; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D007202:Indicators and Reagents; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D011537:Pruritus / Q000139:chemically induced / Q000517:prevention & control; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D006633:Histamine Antagonists; C498829:Hrh4 protein, mouse; D007202:Indicators and Reagents; D008070:Lipopolysaccharides; D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; D014409:Tumor Necrosis Factor-alpha; D006632:Histamine; D003094:Collagen