JNJ-39758979 [(R)-4-(3-amino-pyrrolidin-1-yl)-6-isopropyl-pyrimidin-2-ylamine] is a potent histamine H4 receptor (H4R) antagonist with a Ki at the human receptor of 12.5 nM and greater than 80-fold selectivity over other histamine receptors. JNJ-39758979 showed dose-dependent activity in models of asthma and dermatitis, consistent with other H4R antagonists. Preclinical toxicity studies of up to 6 months in rats and 9 months in monkeys indicated an excellent safety profile supporting the clinical testing of the compound. An oral formulation of JNJ-39758979 was studied in a phase 1 human volunteer study to assess safety, pharmacokinetics, and pharmacodynamics. The compound was well tolerated with the exception of dose-dependent nausea, and it exhibited good pharmacokinetics after a single oral dose with a plasma half-life of 124 to 157 hours. Dose-dependent inhibition of histamine-induced eosinophil shape change was detected, suggesting that the H4R was inhibited in vivo.
See article at J Pharmacol Exp Ther 2014, 349:176–184.
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