Development of a Novel Series of Trialkoxyaryl Derivatives as Specific and Competitive Antagonists of Platelet Activating Factor

• Published in: Journal of medicinal chemistry Vol. 38; no. 12; pp. 2130 - 2137
• Main Authors: Beams, Richard M, Blackwell, Geoffrey J, Brockwell, Michael A, Cheesman, Neil J, Demaine, Derek A, Garland, Lawrence G, Hodson, Harold F, Hyde, Richard M, Islip, Peter J
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.06.1995; Amer Chemical Soc
• Subjects: Animals; Binding Sites; Blood Platelets - drug effects; Blood Platelets - metabolism; Cells, Cultured; Chemistry, Medicinal; Life Sciences & Biomedicine; Male; Pharmacology & Pharmacy; Platelet Activating Factor - antagonists & inhibitors; Platelet Aggregation Inhibitors - pharmacology; Quaternary Ammonium Compounds - chemical synthesis; Quaternary Ammonium Compounds - metabolism; Quaternary Ammonium Compounds - pharmacology; Rabbits; Science & Technology; Structure-Activity Relationship; RABBIT PLATELETS; FACTOR PAF; LEUKOCYTES
• DOI: 10.1021/jm00012a012
• ISSN: 0022-2623

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, pK(b) 5.43). Further SAR considerations directed the design to 2-(hexyloxy)-1,3-dimethoxy-5-[4-(4-methylthiazol-5-yl)butyl]benzene (38) (pK(b) 7.14), a novel, specific, and competitive inhibitor of the PAF receptor in rabbit-washed platelets.