Histamine H4 Receptor (H4R) is a member of the G protein-coupled receptor superfamily. Besides, H4R involves in mediating eosinophil shape change and mast cell chemotaxis. Importantly, H4R mRNA and protein are prominently expressed in cells and tissues of the immune system, for example, in mast cells, lymphocytes, and dendritic cells. Moreover, the Study shows that H4 antagonists have utility as anti-inflammatory and immunomodulatory agents. For instance, H4 antagonists block histamine-mediated shape change and chemotaxis in mast cells and eosinophils.

A-943931 is a potent and selective H4R antagonist.

A-943931 binds to histamine H4 receptor (H4R) with pK_i values of 4.6, and 3.8 nM for human and rat H4R, respectively. Besides, A-943931 shows a very slow metabolism in rat and mouse microsomes. Moreover, A-943931 (10 mg/kg for i.v.) also shows good pharmacokinetic properties with a half-life of 2.6 h, and oral bioavailability of 34% in rats. In addition, A-943931 (5 mg/kg for i.v.) shows high oral bioavailability of 90% and half-live of 1.6 h in mice.

A-943931 (s.c. or i.p.) shows anti-inflammatory activity in zymosan-induced peritonitis in mice with the ED₅₀s of 34, and 33 µmol/kg for SC and IP, respectively. Additionally, A-943931 completely blocks clobenpropit-induced scratching responses in mice after IP dosing with an ED₅₀ value of 33 µmol/kg. Moreover, A-943931 (10, 30, 100 µmol/kg; i.p.) blocks pain responses in a model of carrageenan-induced inflammatory pain with an ED₅₀ value of 72 μmol/kg. In addition, In a spinal nerve ligation model assessing neuropathic pain, A-943931 (0-500 μmol/kg; i.p.) shows an effect with an ED₅₀ value of 100 μmol/kg.

All in all, A-943931 is a potent and selective histamine H4 receptor (H4R) antagonist and shows anti-inflammatory and anti-nociceptive efficacy.

Reference:

[1] Ivan Milicic, et al. The FASEB journal homepage. 2009.

[2] Cowart MD, et al. J Med Chem. 2008 Oct 23;51(20):6547-57.