Abstract

The histamine H₄ receptor (H₄R) has been shown to have preclinical involvement in both inflammatory and pruritic responses. JNJ-39758979 [(R)-4-(3-amino-pyrrolidin-1-yl)-6-isopropyl-pyrimidin-2-ylamine] is a potent and selective H₄R antagonist with a K_i at the human receptor of 12.5 ± 2.6 nM and greater than 80-fold selectivity over other histamine receptors. The compound also exhibited excellent selectivity versus other targets. 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 no safety issues were noted in the phase 1 study. JNJ-39758979 exhibited good pharmacokinetics upon oral dosing with a plasma half-life of 124–157 hours after a single oral dose. In addition, dose-dependent inhibition of histamine-induced eosinophil shape change was detected, suggesting that the H₄R was inhibited in vivo. In conclusion, JNJ-39758979 is a potent and selective H₄R antagonist that exhibited good preclinical and phase 1 safety in healthy volunteers with evidence of a pharmacodynamics effect in humans.