Alcaftadine is a broad-spectrum antihistamine displaying a high affinity for histamine H1 and H2 receptors and a lower affinity for H4 receptors. It also exhibits modulatory action on immune cell recruitment and mast cell stabilizing effects. Alcaftadine is an inhibitor of the release of histamine from mast cells. Decreased chemotaxis and inhibition of eosinophil activation has also been demonstrated. LASTACAFT® (alcaftadine ophthalmic solution) indicated for the prevention of itching associated with allergic conjunctivitis.

Histamine is a depressor amine derived by enzymatic decarboxylation of histidine. It is a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a vasodilator, and a centrally acting neurotransmitter. Phosphate salt of jistamine was used as a diagnostic aid for evaluation of gastric acid secretory function. In addition, this compound is used as a positive control in evaluation of allergenic (immediate hypersensitivity or "Type I") skin testing. In addition, histamine is being studied for treatment of multiple sclerosis. It was approved, that histamine physiological functions are mediated by four 7-transmembrane G protein-coupled receptors (H1R, H2R, H3R, H4R) that are all targets of pharmacological intervention. The receptors display molecular heterogeneity and constitutive activity. H1R antagonists are long known antiallergic and sedating drugs, whereas the H2R led to the development of H2R-antagonists that revolutionized stomach ulcer treatment. The H3R is an auto receptor and heteroreceptor providing negative feedback on histaminergic and inhibition on other neurons. The H4R occurs on immuncompetent cells and the development of anti-inflammatory drugs is anticipated.

JNJ-39758979 is a histamine H4 receptor antagonist which clinical development for asthma and atopic dermatitis was halted during phase II because of the observation of idiosyncratic drug-induced agranulocytosis in two subjects.

Toreforant (JNJ-38518168) is an orally active, selective histamine H4 receptor antagonist. Toreforant was investigated as an agent for the treatment of active rheumatoid arthritis. While some improvement in rheumatoid arthritis signs/symptoms through week 12 was observed in the phase IIa study, no efficacy was observed with toreforant at lower doses in a subsequent phase IIb study. Toreforant has been tested in clinical studies in patients with asthma and psoriasis. Toreforant failed to provide therapeutic benefit in population of patients with uncontrolled, eosinophilic, persistent asthma. Toreforant efficacy at 30 and 60 mg was greater than placebo but did not meet predefined success criterion in patients with moderate-to-severe psoriasis.

(R)-Mequitazine or V0162 (10-[(3R)-1-azabicyclo[2.2.2]oct-3-ylmethyl]-10H-phenothiazine) is an anticholinergic enantiomer of mequitazine, an existing oral racemic antihistamine commercialized for over 30 years. (R)-Mequitazine was found to be an antagonist at muscarinic acetylcholine receptors behaving as an inverse agonist. (R)-Mequitazine was investigated in clinical trials for the treatment of chronic obstructive pulmonary disease, asthma and urinary incontinence.

A-987306 is a new histamine H(4) antagonist. A-987306 is potent in H(4) receptor binding assays (rat H(4), K(i) = 3.4 nM, human H(4) K(i) = 5.8 nM) and demonstrated potent functional antagonism in vitro at human, rat, and mouse H(4) receptors in cell-based FLIPR assays. A-987306 also demonstrated H(4) antagonism in vivo in mice, blocking H(4)-agonist induced scratch responses, and showed anti-inflammatory activity in mice in a peritonitis model. Most interesting was the high potency and efficacy of this compound in blocking pain responses, where it showed an ED(50) of 42 umol/kg (ip) in a rat post-carrageenan thermal hyperalgesia model of inflammatory pain. A-987306 inhibited the scratching response (IC50 = 0.4 umoles/kg, i.p.) with (85%) inhibition seen at 30 umoles/kg, i.p. A-987306 is a potent and selective H4R antagonist with robust antipruritic activity and is a useful tool for further exploration of the role of H4R receptors in vivo.

A-943931 is a potent and selective H4R antagonist with high affinity at both human (Kis = 4.6 nM) and rat (Kis = 3.8 nM) receptors. A-943931 competitively and potently antagonizes rat H4R agonist-mediated responses in [35S]GTPγS binding assays (Kbs = 28 nM) and intracellular calcium mobilization at rat and human receptors (Kbs from 5-10 nM). When tested in vivo in a mouse model of clobenpropit (10 nM, i.d.) induced scratching, A-943931 inhibited the scratching response (IC50 = 26 umoles/kg, i.p.) with significant inhibition (69%) at the highest tested dose (30 umoles/kg, i.p.). A-943931 is a potent and selective H4R antagonist with robust antipruritic activity and is a useful tool for further exploration of the role of H4R receptors in vivo.