PT  - JOURNAL ARTICLE
AU  - Thurmond, Robin L.
AU  - Chen, Bin
AU  - Dunford, Paul J.
AU  - Greenspan, Andrew J.
AU  - Karlsson, Lars
AU  - La, David
AU  - Ward, Peter
AU  - Xu, Xie L.
TI  - Clinical and Preclinical Characterization of the Histamine H&lt;sub&gt;4&lt;/sub&gt; Receptor Antagonist JNJ-39758979
AID  - 10.1124/jpet.113.211714
DP  - 2014 May 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 176--184
VI  - 349
IP  - 2
4099  - http://jpet.aspetjournals.org/content/349/2/176.short
4100  - http://jpet.aspetjournals.org/content/349/2/176.full
SO  - J Pharmacol Exp Ther2014 May 01; 349
AB  - 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 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 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.