title: INCB38579, a novel and potent histamine H₄ receptor small molecule antagonist with anti-inflammatory pain and anti-pruritic functions.
abstract: The histamine H₄ receptor mediates several histamine-induced cellular functions of leukocytes, including cell migration and cytokine production. Recent studies suggest that histamine signaling through the histamine H₄ receptor can also have anti-pruritic and anti-nociceptive functions. 1-(7-(2-amino-6-(4-methylpiperazin-1-yl) pyrimidin-4-yl)-3, 4-dihdroisoquinolin-2(1H)-yl)-2-cyclopentylethanone (INCB38579) is a novel small molecule antagonist of the human and rodent histamine H₄ receptors with at least 80-fold selectivity over the human histamine H₁, H₂ and H₃ receptors, and has good pharmacokinetic properties in rats and mice. The compound is potent in inhibiting histamine binding to and signaling through the recombinant human, mouse and rat histamine H₄ receptors and blocks the histamine-induced migration of human and mouse dendritic cells, as well as the cell shape change and migration of human eosinophils. INCB38579 and histamine may have separate but overlapping binding sites on the human histamine H₄ receptor. This novel inhibitor is efficacious when evaluated in two previously established in vivo models for histamine H₄ receptor activity (histamine-induced itch in mice and carrageenan-induced acute inflammatory pain in rats). When examined in formalin-induced pain models, INCB38579 significantly reduces the sustained inflammatory pain experienced by rats and mice. A good correlation between the protein binding adjusted potency from in vitro studies and its analgesic effect in vivo was observed. These results suggest that INCB38579 can serve as a useful tool for pharmacologic characterization of the histamine H₄ receptor and further support the hypothesis that targeting the histamine H₄ receptor may provide new therapeutic agents for various chronic inflammatory diseases, including inflammatory pain.
authors.affiliation: Incyte Corporation, Rt 141 & Henry Clay Road, Wilmington, DE 19880, USA. nshin@incyte.com
authors.forename: Niu
authors.initials: N
authors.lastname: Shin
authors.forename: Maryanne
authors.initials: M
authors.lastname: Covington
authors.forename: Di
authors.initials: D
authors.lastname: Bian
authors.forename: Jincong
authors.initials: J
authors.lastname: Zhuo
authors.forename: Kevin
authors.initials: K
authors.lastname: Bowman
authors.forename: Yanlong
authors.initials: Y
authors.lastname: Li
authors.forename: Maxim
authors.initials: M
authors.lastname: Soloviev
authors.forename: Ding-Quan
authors.initials: DQ
authors.lastname: Qian
authors.forename: Patricia
authors.initials: P
authors.lastname: Feldman
authors.forename: Lynn
authors.initials: L
authors.lastname: Leffet
authors.forename: Xin
authors.initials: X
authors.lastname: He
authors.forename: Kathy
authors.initials: K
authors.lastname: He Wang
authors.forename: Kristin
authors.initials: K
authors.lastname: Krug
authors.forename: Dan
authors.initials: D
authors.lastname: Bell
authors.forename: Philip
authors.initials: P
authors.lastname: Czerniak
authors.forename: Zhijing
authors.initials: Z
authors.lastname: Hu
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Swamy
authors.initials: S
authors.lastname: Yeleswaram
authors.forename: Wenqing
authors.initials: W
authors.lastname: Yao
authors.forename: Robert
authors.initials: R
authors.lastname: Newton
authors.forename: Peggy
authors.initials: P
authors.lastname: Scherle
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D000982:Antipruritics / Q000097:blood / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D020013:Calcium Signaling / Q000187:drug effects; D002478:Cells, Cultured; D002630:Chemotactic Factors / Q000097:blood / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D057809:HEK293 Cells; D006633:Histamine Antagonists / Q000097:blood / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007107:Immune System / Q000166:cytology / Q000187:drug effects; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D007546:Isoquinolines / Q000097:blood / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011537:Pruritus / Q000139:chemically induced / Q000188:drug therapy; D011743:Pyrimidines / Q000097:blood / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011968:Receptors, Histamine / Q000235:genetics / Q000378:metabolism; D000074040:Receptors, Histamine H4; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C571834:1-(7-(2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-cyclopentylethanone; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000982:Antipruritics; D002630:Chemotactic Factors; C418607:HRH4 protein, human; D006633:Histamine Antagonists; C498829:Hrh4 protein, mouse; C498828:Hrh4 protein, rat; D007546:Isoquinolines; D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; D011994:Recombinant Proteins