A novel class of platelet activating factor (PAF) antagonists. I. Synthesis and structure-activity studies on PAF-sulfonamide isosteres.
New platelet activating factor (PAF) antagonists, 3 were synthesized by replacing the charged phosphate and trimethylammonium moieties with sulfonamide and heterocyclic quaternary ammonium functionalities, respectively (PAF-sulfonamide isosteres). Darmstoff phosphatidic acid analogues of this class (Darmstoff-sulfonamide isosteres), 6 were also synthesized. The activity of these compounds as PAF antagonists was evaluated from their in vitro inhibitory effect on PAF-induced platelet aggregation in rabbit platelet-rich plasma. Among the compounds tested, some of the 2-methoxypropane derivatives with an octadecylcarbamoyloxy or octadecylcarbamoylthio side chain at the 1-position and a propylsulfonamide function bearing a terminal polar substituent such as a quaternary quinolinium or substituted quinolinium group at the 3-position were found to be the most potent (IC50 = 0.3-0.6 microM).
Tsuri
T
T
Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Haga
N
N
Matsui
T
T
Kamata
S
S
Kakushi
H
H
Uchida
K
K
D000818:Animals; D066298:In Vitro Techniques; D007536:Isomerism; D008297:Male; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000737:chemistry; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011817:Rabbits; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology
D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D013449:Sulfonamides