A novel class of platelet activating factor (PAF) antagonists. I. Synthesis and structure-activity studies on PAF-sulfonamide isosteres. |
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Authors: | T Tsuri N Haga T Matsui S Kamata H Kakushi K Uchida |
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Institution: | Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan. |
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Abstract: | 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). |
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