title: Structure-activity studies on a series of a 2-aminopyrimidine-containing histamine H4 receptor ligands.
abstract: A series of 2-aminopyrimidines was synthesized as ligands of the histamine H4 receptor (H4R). Working in part from a pyrimidine hit that was identified in an HTS campaign, SAR studies were carried out to optimize the potency, which led to compound 3, 4- tert-butyl-6-(4-methylpiperazin-1-yl)pyrimidin-2-ylamine. We further studied this compound by systematically modifying the core pyrimidine moiety, the methylpiperazine at position 4, the NH2 at position 2, and positions 5 and 6 of the pyrimidine ring. The pyrimidine 6 position benefited the most from this optimization, especially in analogs in which the 6- tert-butyl was replaced with aromatic and secondary amine moieties. The highlight of the optimization campaign was compound 4, 4-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]benzonitrile, which was potent in vitro and was active as an anti-inflammatory agent in an animal model and had antinociceptive activity in a pain model, which supports the potential of H 4R antagonists in pain.
authors.affiliation: Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6100, USA. Robert.j.altenbach@abbott.com
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Altenbach
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Adair
authors.forename: Brian M
authors.initials: BM
authors.lastname: Bettencourt
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Black
authors.forename: Shannon R
authors.initials: SR
authors.lastname: Fix-Stenzel
authors.forename: Sujatha M
authors.initials: SM
authors.lastname: Gopalakrishnan
authors.forename: Gin C
authors.initials: GC
authors.lastname: Hsieh
authors.forename: Huaqing
authors.initials: H
authors.lastname: Liu
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Michael J
authors.initials: MJ
authors.lastname: McPherson
authors.forename: Ivan
authors.initials: I
authors.lastname: Milicic
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Miller
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Vortherms
authors.forename: Usha
authors.initials: U
authors.lastname: Warrior
authors.forename: Jill M
authors.initials: JM
authors.lastname: Wetter
authors.forename: Neil
authors.initials: N
authors.lastname: Wishart
authors.forename: David G
authors.initials: DG
authors.lastname: Witte
authors.forename: Prisca
authors.initials: P
authors.lastname: Honore
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Esbenshade
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Hancock
authors.forename: Jorge D
authors.initials: JD
authors.lastname: Brioni
authors.forename: Marlon D
authors.initials: MD
authors.lastname: Cowart
mesh_terms: D000818:Animals; D015415:Biomarkers; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006965:Hyperplasia / Q000139:chemically induced / Q000517:prevention & control; D008024:Ligands; D008124:Locomotion / Q000187:drug effects; D051379:Mice; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011968:Receptors, Histamine / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D015415:Biomarkers; D006633:Histamine Antagonists; D008024:Ligands; D011743:Pyrimidines; D011968:Receptors, Histamine; C012180:2-aminopyrimidine