jnj39758979

JNJ-39758979 is a selective, high-affinity histamine H4 receptor antagonist with a Ki of 12.5 nM.

Signaling Pathways >> GPCR/G Protein >> Histamine Receptor

Signaling Pathways >> Immunology/Inflammation >> Histamine Receptor

Research Areas >> Neurological Disease

Ki: 12.5 nM (histamine H4 receptor)[1]

JNJ-39758979 is a selective, high-affinity histamine H4 receptor antagonist with a Ki of 12.5 nM. The affinity of JNJ-39758979 for the rat (Ki=188 nM) and guinea pig H4R (Ki=306 nM) is moderate, and JNJ-39758979 has little if any affinity for the dog H4R (Ki≥10 μM). JNJ-39758979 is metabolically stable (t1/2 >120 min) when incubated in vitro with human, rat, dog, or monkey liver microsomes[1].

JNJ-39758979 shows dose-proportional pharmacokinetic (PK) in rat in the range of 2 to 500 mpK. JNJ-39758979 rapidly reaches the kidneys and liver (mean tmax=2.0 h). The elimination of JNJ-39758979 is slow from the brain, liver, and kidneys, with mean t1/2 values of 42.5, 22.3, and 20.5 h, respectively. The highest exposure (based on Cmax and AUC0-inf values) is observed in the liver followed by the kidney and brain. Tissue-to-plasma ratios for liver and kidney range from 23.2 to 95.8; the tissue-to-plasma ratios in brain increases with time from 0.256 to 22.7 up to 48 h after dosing. JNJ-39758979 is able to inhibit histamine-induced itch at doses of 5 and 20 mg/kg in mice. JNJ-39758979 exhibits dose-dependent inhibition of the clinical score in a mouse collagen-induced arthritis model[1].

The model of histamine-induced scratching in C57/bl6 mice (n=6 to 8 per group) is used to judge the antipruritic effects of JNJ-39758979. JNJ-39758979 is given p.o. in 20% hydroxypropyl-β-cyclodextran 30 min before an intradermal injection of histamine (100 μg). Bouts of scratching are calculated using an automated system. Immediately after histamine injection, mice are placed in containers above a solenoid, and magnets previously placed on the mouse ear generate scratch-specific signals that are counted over a 20 min time span[1].

[1]. Savall BM, et al. Discovery and SAR of 6-alkyl-2,4-diaminopyrimidines as histamine H₄ receptor antagonists. J Med Chem. 2014 Mar 27;57(6):2429-39.

Loratadine | Histamine | Pitolisant hydrochloride | Cimetidine | Osthole | Clemastine fumarate | Ebrotidine | JNJ-7777120 | Famotidine | Cetirizine Dihydrochloride | Desloratadine | Ketotifen fumarate | Lodoxamide | Meclizine dihydrochloride | Chlorpheniramine maleate