title: Development of a novel series of trialkoxyaryl derivatives as specific and competitive antagonists of platelet activating factor.
abstract: The synthesis and structure-activity relationship (SAR) analysis of a novel series of trialkoxyaryl derivatives, as specific and competitive inhibitors of platelet activating factor (PAF), are described. Molecular modeling comparisons of PAF with the known antagonists Ginkgolide B and L-652731 led to the selection of N-[2-[(3,4,5-trimethoxybenzoyl)oxy]ethyl]-N,N,N-trimethylammonium iodide (1) from the Wellcome registry of compounds and to the synthesis of the lead compound N-[2-[[4-(hexyloxy)-3,5-dimethoxybenzoyl]oxy]ethyl]-N,N,N- trimethylammonium iodide (3, pKb 5.43). Further SAR considerations directed the design to 2-(hexyloxy)-1,3-dimethoxy-5-[4-(4-methylthiazol-5-yl)butyl] benzene (38) (pKb 7.14), a novel, specific, and competitive inhibitor of the PAF receptor in rabbit-washed platelets.
authors.affiliation: Department of Medicinal Chemistry, Wellcome Research Laboratories, Beckenham, Kent, England.
authors.forename: D A
authors.initials: DA
authors.lastname: Sawyer
authors.forename: R M
authors.initials: RM
authors.lastname: Beams
authors.forename: G J
authors.initials: GJ
authors.lastname: Blackwell
authors.forename: M A
authors.initials: MA
authors.lastname: Brockwell
authors.forename: N J
authors.initials: NJ
authors.lastname: Cheesman
authors.forename: D A
authors.initials: DA
authors.lastname: Demaine
authors.forename: L G
authors.initials: LG
authors.lastname: Garland
authors.forename: H F
authors.initials: HF
authors.lastname: Hodson
authors.forename: R M
authors.initials: RM
authors.lastname: Hyde
authors.forename: P J
authors.initials: PJ
authors.lastname: Islip
mesh_terms: D000818:Animals; D001665:Binding Sites; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D008297:Male; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011817:Rabbits; D013329:Structure-Activity Relationship
chemical_list: D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D000644:Quaternary Ammonium Compounds