title: Rotationally constrained 2,4-diamino-5,6-disubstituted pyrimidines: a new class of histamine H4 receptor antagonists with improved druglikeness and in vivo efficacy in pain and inflammation models.
abstract: A new structural class of histamine H 4 receptor antagonists (6-14) was designed based on rotationally restricted 2,4-diaminopyrimidines. Series compounds showed potent and selective in vitro H 4 antagonism across multiple species, good CNS penetration, improved PK properties compared to reference H 4 antagonists, functional H 4 antagonism in cellular and in vivo pharmacological assays, and in vivo anti-inflammatory and antinociceptive efficacy. One compound, 10 (A-943931), combined the best features of the series in a single molecule and is an excellent tool compound to probe H 4 pharmacology. It is a potent H 4 antagonist in functional assays across species (FLIPR Ca (2+) flux, K b < 5.7 nM), has high (>190x) selectivity for H 4, and combines good PK in rats and mice (t 1/2 of 2.6 and 1.6 h, oral bioavailability of 37% and 90%) with anti-inflammatory activity (ED 50 = 37 micromol/kg, mouse) and efficacy in pain models (thermal hyperalgesia, ED 50 = 72 micromol/kg, rat).
authors.affiliation: Department of Neuroscience Research, Abbott Laboratories, Abbott Park, Illinois 60064-6123, USA. marlon.d.cowart@abbott.com
authors.forename: Marlon D
authors.initials: MD
authors.lastname: Cowart
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Altenbach
authors.forename: Huaqing
authors.initials: H
authors.lastname: Liu
authors.forename: Gin C
authors.initials: GC
authors.lastname: Hsieh
authors.forename: Irene
authors.initials: I
authors.lastname: Drizin
authors.forename: Ivan
authors.initials: I
authors.lastname: Milicic
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Miller
authors.forename: David G
authors.initials: DG
authors.lastname: Witte
authors.forename: Neil
authors.initials: N
authors.lastname: Wishart
authors.forename: Shannon R
authors.initials: SR
authors.lastname: Fix-Stenzel
authors.forename: Michael J
authors.initials: MJ
authors.lastname: McPherson
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Adair
authors.forename: Jill M
authors.initials: JM
authors.lastname: Wetter
authors.forename: Brian M
authors.initials: BM
authors.lastname: Bettencourt
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: James P
authors.initials: JP
authors.lastname: Sullivan
authors.forename: Prisca
authors.initials: P
authors.lastname: Honore
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Esbenshade
authors.forename: Jorge D
authors.initials: JD
authors.lastname: Brioni
mesh_terms: D000588:Amines / Q000737:chemistry*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000145:classification / Q000627:therapeutic use; D004195:Disease Models, Animal; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000145:classification / Q000627:therapeutic use*; D008024:Ligands; D051379:Mice; D015394:Molecular Structure; D010146:Pain / Q000188:drug therapy*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000145:classification / Q000627:therapeutic use; D051381:Rats; D011968:Receptors, Histamine / Q000378:metabolism*
chemical_list: D000588:Amines; D000893:Anti-Inflammatory Agents; D006633:Histamine Antagonists; D008024:Ligands; D011743:Pyrimidines; D011968:Receptors, Histamine; C030986:pyrimidine