title: Synthesis and QSAR of quinazoline sulfonamides as highly potent human histamine H4 receptor inverse agonists.
abstract: Hit optimization of the class of quinazoline containing histamine H(4) receptor (H(4)R) ligands resulted in a sulfonamide substituted analogue with high affinity for the H(4)R. This moiety leads to improved physicochemical properties and is believed to probe a distinct H(4)R binding pocket that was previously identified using pharmacophore modeling. By introducing a variety of sulfonamide substituents, the H(4)R affinity was optimized. The interaction of the new ligands, in combination with a set of previously published quinazoline compounds, was described by a QSAR equation. Pharmacological studies revealed that the sulfonamide analogues have excellent H(4)R affinity and behave as inverse agonists at the human H(4)R. In vivo evaluation of the potent 2-(6-chloro-2-(4-methylpiperazin-1-yl)quinazoline-4-amino)-N-phenylethanesulfonamide (54) (pK(i) = 8.31 +/- 0.10) revealed it to have anti-inflammatory activity in an animal model of acute inflammation.
authors.affiliation: Griffin Discoveries BV, Department of Medicinal Chemistry, Room P-246, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Rogier A
authors.initials: RA
authors.lastname: Smits
authors.forename: Maristella
authors.initials: M
authors.lastname: Adami
authors.forename: Enade P
authors.initials: EP
authors.lastname: Istyastono
authors.forename: Obbe P
authors.initials: OP
authors.lastname: Zuiderveld
authors.forename: Cindy M E
authors.initials: CM
authors.lastname: van Dam
authors.forename: Frans J J
authors.initials: FJ
authors.lastname: de Kanter
authors.forename: Aldo
authors.initials: A
authors.lastname: Jongejan
authors.forename: Gabriella
authors.initials: G
authors.lastname: Coruzzi
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
authors.forename: Iwan J P
authors.initials: IJ
authors.lastname: de Esch
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D002351:Carrageenan; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D006801:Humans; D007700:Kinetics; D008956:Models, Chemical; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D011968:Receptors, Histamine / Q000378:metabolism; D000074040:Receptors, Histamine H4; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; C418607:HRH4 protein, human; D011799:Quinazolines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; D013449:Sulfonamides; D002351:Carrageenan