Histamine exhibits its functions through four known G-protein coupled receptors, the H1, H2, H3, and H4 receptors. Some histamine receptor (H1R) antagonists are used for the treatment of allergic inflammatory responses. Additionally, the histamine H3 receptor (H3R) localizes in the CNS. It regulates the release and synthesis of histamine and modulates other neurotransmitters. What’s more, the Histamine 4 receptor (H4R) has high homology to the H3R (35%) but much lower homology to H1 and H2 receptors.

In this article, we will introduce a potent histamine H4 antagonist, A-987306.

As a potent histamine H4 antagonist, A-987306 exhibits Ki values of 3.4 nM and 5.8 nM for rat H4, and human H4, respectively.  Besides, A-987306 is 620-fold, >1600-fold, and 162-fold selective for the human H4R over the human H1, H2, and H3 receptors.

Next, in vivo, the pharmacokinetic profile of A-987306 is displayed by i.v, i.p, and oral administration. In SD rats, After i.p dosing, the compound exhibits a favorable fractional bioavailability (Fip/iv=72%). Additionally, it exhibits half-life (t1/2=4.7 h), and a Cmax of 1.73 µM at a Tmax of 0.25 h after dosing.

Besides, after oral dosing, A-987306 displays a moderate fractional oral bioavailability (Fip/iv=26%) with a half-life of 3.7 h and a Cmax of 0.30 µM at a Tmax of 1.5 h.

In the mouse itch model, in a pharmacological test displays for in vivo H4R antagonism with A-987306.

A-987306 reduces scratch responses in mice with an ED50 of 0.36 µmol/kg. Furthermore, the plasma levels of A-987306 near the ED50 (0.3 µmol/kg) supports a high level of in vivo potency in this model.

Lastly, H4R antagonists have anti-inflammatory activity in a zymosan-induced peritonitis model. Zymosan intraperitoneal dosing can induce migration of polymorphonuclear leukocyte (PMN)
cells to the peritoneum. In this model, A-987306 blocks the zymosan-induced neutrophil influx at a dose of 100 µmol/kg, with a level of efficacy equal to the standard indomethacin dosed at
10 mpk. The IC50 of A-987306 is 125 µmol/kg in mice in this model.

In conclusion, A-987306 is an oral bioavailable histamine H4 antagonist and shows anti-inflammatory activity in mice peritonitis model.


Huaqing Liu, et al. J. Med. Chem., 2008, 51 (22), pp 7094-7098