Functional Profiling of 2-Aminopyrimidine Histamine H4 Receptor Modulators

• Published in: Journal of medicinal chemistry Vol. 58; no. 18; pp. 7119 - 7127
• Main Authors: Tichenor, Mark S, Thurmond, Robin L, Venable, Jennifer D, Savall, Brad M
• Format: Journal Article
• Language: English
• Published: United States 24.09.2015
• Subjects: Aminopyridines - chemistry; Aminopyridines - pharmacology; Aminopyridines - therapeutic use; Animals; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - metabolism; Asthma - drug therapy; Asthma - metabolism; Dermatitis, Atopic - drug therapy; Dermatitis, Atopic - metabolism; Drug Partial Agonism; Histamine Agonists - chemistry; Histamine Agonists - pharmacology; Histamine Agonists - therapeutic use; Histamine Antagonists - chemistry; Histamine Antagonists - pharmacology; Histamine Antagonists - therapeutic use; Humans; Hypersensitivity - drug therapy; Hypersensitivity - metabolism; Receptors, G-Protein-Coupled - metabolism; Receptors, Histamine - metabolism; Receptors, Histamine H4; Structure-Activity Relationship
• ISSN: 1520-4804
• DOI: 10.1021/acs.jmedchem.5b00516

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.