Histamine H4 receptor antagonists

Jablonowski JA, Grice CA, Chai W, et al. The first potent and selective non-imidazole human histamine H4 receptor antagonist. / Med Chem 2003 46 3957-60. 

Thurmond RL, Desai PJ, Dunford PJ, et al. A potent and selective histamine H4 receptor antagonist with anti-inflammatory properties. J Pharmacol Exp Ther 2004 309 404-413. 

In 2011, in the synthesis of a new series of tricyclic pyrimidine compounds as histamine H4 receptor antagonists, Savall and coworkers first tried to convert the pyrimidinone compound to the chloropyrimidine compound for the subsequent S Ar displacement reaction. However, this attempted chlorination was not successful with a variety of chlorination reagents. Alternatively, they synthesized this target compound via direct amination of the tautomerizable heterocycle using BOP in the presence of DBU in DMF (11BMCL6577). 

In particular, the discovery of a fourth HR (H4) and its expression on numerous immune and inflammatory cells has prompted a re-evalu-ation of the actions of histamine, suggesting a new potential for H4-receptor antagonists and a possible synergy between Hj- and H4-receptor antagonists in targeting various inflammatory conditions [98]. 

The histamine H4-receptor which was discovered in 2001 has been shown to have a role in chemo-taxis and mediator release in various types of immune cells including mast cells, eosinophils, dendritic cells and T cells. H4-receptor antagonists have been shown to have anti-inflammatory properties and efficacy in a number of disease models, such as those for asthma and colitis in vivo. Cinnarizine has a high affinity for the H4-receptor. Recently other H4-receptor antagonists have been developed with high receptor affinity and specificity. The first few studies into the function of H4-receptors suggested... 

Watanabe, M., Kazuta, Y., Hayashi, H., Yamada, S., Matsuda, A., Shuto, D. Stereochemical diversity-oriented conformational restriction strategy. Development of potent histamine H3 and/or H4 receptor antagonists with an imidazolylcyclopropane structure. J. Med. Chem. 2006,49, 5587-5596. 

Compounds that competitively block histamine at H4 receptors have been used in the treatment of allergic conditions for many years, and many Hi antagonists are currently marketed in the USA. Many are available without prescription, both alone and in combination formulations such as "cold pills" and sleep aids (see Chapter 63). 

Certain Hi antagonists, eg, cetirizine, inhibit mast cell release of histamine and some other mediators of inflammation. This action is not due to H -receptor blockade and may reflect an H4-receptor effect (see below). The mechanism is not fully understood but could play a role in the beneficial effects of these drugs in the treatment of allergies such as rhinitis. A few H4 antagonists (eg, terfenadine, acrivastine) have been shown to inhibit the P-glycoprotein transporter found in cancer cells, the epithelium of the gut, and the capillaries of the brain. The significance of this effect is not known. 

The development of H2-receptor antagonists was based on the observation that H4 antagonists had no effect on histamine-induced acid secretion in the stomach. Molecular manipulation of the histamine molecule resulted in drugs that blocked acid secretion and had no H4-agonist or antagonist effects. Like the other histamine receptors, the H2 receptor displays constitutive activity, and some H2 blockers are inverse agonists. 

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