Development of a novel series of trialkoxyaryl derivatives as specific and competitive antagonists of platelet activating factor.
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.
Sawyer
D A
DA
Department of Medicinal Chemistry, Wellcome Research Laboratories, Beckenham, Kent, England.
Beams
R M
RM
Blackwell
G J
GJ
Brockwell
M A
MA
Cheesman
N J
NJ
Demaine
D A
DA
Garland
L G
LG
Hodson
H F
HF
Hyde
R M
RM
Islip
P J
PJ
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
D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D000644:Quaternary Ammonium Compounds