title: Preparation and biological evaluation of indole, benzimidazole, and thienopyrrole piperazine carboxamides: potent human histamine h(4) antagonists.
abstract: Three series of H(4) receptor ligands, derived from indoly-2-yl-(4-methyl-piperazin-1-yl)-methanones, have been synthesized and their structure-activity relationships evaluated for activity at the H(4) receptor in competitive binding and functional assays. In all cases, substitution of small lipophilic groups in the 4 and 5-positions led to increased activity in a [(3)H]histamine radiolabeled ligand competitive binding assay. In vitro metabolism and initial pharmacokinetic studies were performed on selected compounds leading to the identification of indole 8 and benzimidazole 40 as potent H(4) antagonists with the potential for further development. In addition, both 8 and 40 demonstrated efficacy in in vitro mast cell and eosinophil chemotaxis assays.
authors.affiliation: Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego, California 92121, USA. jvenable@prdus.jnj.com
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Venable
authors.forename: Hui
authors.initials: H
authors.lastname: Cai
authors.forename: Wenying
authors.initials: W
authors.lastname: Chai
authors.forename: Curt A
authors.initials: CA
authors.lastname: Dvorak
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Grice
authors.forename: Jill A
authors.initials: JA
authors.lastname: Jablonowski
authors.forename: Chandra R
authors.initials: CR
authors.lastname: Shah
authors.forename: Annette K
authors.initials: AK
authors.lastname: Kwok
authors.forename: Kiev S
authors.initials: KS
authors.lastname: Ly
authors.forename: Barbara
authors.initials: B
authors.lastname: Pio
authors.forename: Jianmei
authors.initials: J
authors.lastname: Wei
authors.forename: Pragnya J
authors.initials: PJ
authors.lastname: Desai
authors.forename: Wen
authors.initials: W
authors.lastname: Jiang
authors.forename: Steven
authors.initials: S
authors.lastname: Nguyen
authors.forename: Ping
authors.initials: P
authors.lastname: Ling
authors.forename: Sandy J
authors.initials: SJ
authors.lastname: Wilson
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Dunford
authors.forename: Robin L
authors.initials: RL
authors.lastname: Thurmond
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Lovenberg
authors.forename: Lars
authors.initials: L
authors.lastname: Karlsson
authors.forename: Nicholas I
authors.initials: NI
authors.lastname: Carruthers
authors.forename: James P
authors.initials: JP
authors.lastname: Edwards
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004804:Eosinophils / Q000187:drug effects; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D008407:Mast Cells / Q000187:drug effects; D051379:Mice; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4
chemical_list: D001562:Benzimidazoles; C418607:HRH4 protein, human; D006633:Histamine Antagonists; D007211:Indoles; D010879:Piperazines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4