RT Journal Article SR Electronic T1 Clinical and Preclinical Characterization of the Histamine H4 Receptor Antagonist JNJ 39758979 JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP jpet.113.211714 DO 10.1124/jpet.113.211714 A1 Robin Thurmond A1 Bin Chen A1 Paul J Dunford A1 Andrew J. Greenspan A1 Lars Karlsson A1 David La A1 Peter Ward A1 Xie L Xu YR 2014 UL http://jpet.aspetjournals.org/content/early/2014/02/18/jpet.113.211714.abstract AB The histamine H4 receptor (H4R) has been shown to be involved in both inflammatory and pruritic responses preclinically. JNJ 39758979 is a potent and selective H4R antagonist with a Ki 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 h 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.