PT  - JOURNAL ARTICLE
AU  - Robin Thurmond
AU  - Bin Chen
AU  - Paul J Dunford
AU  - Andrew J. Greenspan
AU  - Lars Karlsson
AU  - David La
AU  - Peter Ward
AU  - Xie L Xu
TI  - Clinical and Preclinical Characterization of the Histamine H<sub>4</sub> Receptor Antagonist JNJ 39758979
AID  - 10.1124/jpet.113.211714
DP  - 2014 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.113.211714
4099  - http://jpet.aspetjournals.org/content/early/2014/02/18/jpet.113.211714.short
4100  - http://jpet.aspetjournals.org/content/early/2014/02/18/jpet.113.211714.full
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.