pf-3893787 and Asthma

Histamine is an important endogenous signaling molecule that is involved in a number of physiological processes including allergic reactions, gastric acid secretion, neurotransmitter release, and inflammation. The biological effects of histamine are mediated by four histamine receptors with distinct functions and distribution profiles (H1-H4). The most recently discovered histamine receptor (H4) has emerged as a promising drug target for treating inflammatory diseases. A detailed understanding of the role of the H4 receptor in human disease remains elusive, in part because low sequence similarity between the human and rodent H4 receptors complicates the translation of preclinical pharmacology to humans. This review provides an overview of H4 drug discovery programs that have studied cross-species structure-activity relationships, with a focus on the functional profiling of the 2-aminopyrimidine chemotype that has advanced to the clinic for allergy, atopic dermatitis, asthma, and rheumatoid arthritis.

Topics: Aminopyridines; Animals; Arthritis, Rheumatoid; Asthma; Dermatitis, Atopic; Drug Partial Agonism; Histamine Agonists; Histamine Antagonists; Humans; Hypersensitivity; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Structure-Activity Relationship

Histamine H4 receptor (H4R) has become a promising target for immuno-inflammatory diseases, such as allergic rhinitis, asthma or dermal allergies. Its distribution pattern in immune cells and the preclinical data obtained from different biological systems using diverse histamine H4 modulators (1) suggest a key role of H4R in immunity and in inflammatory cell trafficking. Recent results with UR-63325, the first H4R antagonist from which clinical data has been reported (2), confirm the feasibility of complete H4R blocking in humans without limiting safety concerns. Also, H4R blockade results in clear pharmacodynamic effects in relevant human cells, e.g. eosinophils. It is believed that allergic rhinitis and asthma are manifestations of one unique syndrome in two parts of the respiratory tract. Dermal allergies are also recognized as related manifestations in a different location. The coexistence of allergic-related diseases in the same patients could permit a single treatment approach e.g.. the systemic use of H4R antagonists. Further clinical studies are needed to establish the role of H4R antagonists in the treatment of allergic diseases.

Topics: Asthma; Drug Delivery Systems; Eosinophils; Humans; Hypersensitivity; Optical Imaging; Pyrimidines; Pyrrolidines; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4