title: Clinical and preclinical characterization of the histamine H(4) receptor antagonist JNJ-39758979.
abstract: The histamine H4 receptor (H(4)R) 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 H(4)R 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 H(4)R 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 H(4)R antagonist that exhibited good preclinical and phase 1 safety in healthy volunteers with evidence of a pharmacodynamics effect in humans.
authors.affiliation: Janssen Research & Development, L.L.C., San Diego, California.
authors.forename: Robin L
authors.initials: RL
authors.lastname: Thurmond
authors.forename: Bin
authors.initials: B
authors.lastname: Chen
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Dunford
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Greenspan
authors.forename: Lars
authors.initials: L
authors.lastname: Karlsson
authors.forename: David
authors.initials: D
authors.lastname: La
authors.forename: Peter
authors.initials: P
authors.lastname: Ward
authors.forename: Xie L
authors.initials: XL
authors.lastname: Xu
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D001249:Asthma / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D048430:Cell Shape / Q000187:drug effects; D003877:Dermatitis, Contact / Q000188:drug therapy / Q000209:etiology / Q000276:immunology; D004311:Double-Blind Method; D004804:Eosinophils / Q000187:drug effects / Q000473:pathology; D005260:Female; D006801:Humans; D017879:Isothiocyanates; D008252:Macaca fascicularis; D008297:Male; D010047:Ovalbumin; D011743:Pyrimidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; D013844:Thiazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: C568132:(2-(2,6-dichlorobenzyl)thiazolo(5,4-d)pyrimidin-7-yl)-(4-trifluoromethylphenyl)amine; D000893:Anti-Inflammatory Agents; C418607:HRH4 protein, human; D017879:Isothiocyanates; D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; D013844:Thiazoles; C037152:isothiocyanic acid; D010047:Ovalbumin