title: Functional Profiling of 2-Aminopyrimidine Histamine H4 Receptor Modulators.
abstract: 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.
authors.affiliation: Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Tichenor
authors.affiliation: Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States.
authors.forename: Robin L
authors.initials: RL
authors.lastname: Thurmond
authors.affiliation: Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States.
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Venable
authors.affiliation: Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States.
authors.forename: Brad M
authors.initials: BM
authors.lastname: Savall
mesh_terms: D000631:Aminopyridines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism; D001249:Asthma / Q000188:drug therapy / Q000378:metabolism; D003876:Dermatitis, Atopic / Q000188:drug therapy / Q000378:metabolism; D054333:Drug Partial Agonism; D017442:Histamine Agonists / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D006633:Histamine Antagonists / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D006967:Hypersensitivity / Q000188:drug therapy / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D011968:Receptors, Histamine / Q000378:metabolism*; D000074040:Receptors, Histamine H4; D013329:Structure-Activity Relationship
chemical_list: D000631:Aminopyridines; C418607:HRH4 protein, human; D017442:Histamine Agonists; D006633:Histamine Antagonists; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4