title: A novel class of platelet activating factor (PAF) antagonists. II. Modification of the 2-position of the glycerol backbone of PAF-sulfonamide isosteres.
abstract: In a continuing effort to obtain more potent platelet activating factor (PAF) antagonists, we tried to synthesize a series of PAF-sulfonamide isosteres in which the substituent at the 2-position was modified to an acetoxy equivalent other than the methoxy group. These modifications produced highly active PAF antagonists. Compound 3-[2-(5-methyl-2H-tetrazol-2-yl)-3-(octadecylcarbamoyloxy) propylaminosulfonyl]propylquinolinium iodide (52) showed the most potent activity in the in vitro inhibitory effect on PAF-induced platelet aggregation in rabbit platelet-rich plasma (IC50 = 125 nM) and also in the in vivo protective effect on PAF-induced lethality in mice, with prolonged duration of action. Optically active enantiomers of this compound were synthesized and the (S)-(-)-isomer (IC50 = 87 nM) was found to be three times more potent that the (R)-(+)-isomer (IC50 = 289 nM), clearly exemplifying the enantioselectivity in the PAF-antagonist action of this novel compound.
authors.affiliation: Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Tsuri
authors.forename: T
authors.initials: T
authors.lastname: Matsui
authors.forename: N
authors.initials: N
authors.lastname: Haga
authors.forename: S
authors.initials: S
authors.lastname: Kamata
authors.forename: S
authors.initials: S
authors.lastname: Hagishita
authors.forename: K
authors.initials: K
authors.lastname: Takahashi
authors.forename: H
authors.initials: H
authors.lastname: Kakushi
authors.forename: K
authors.initials: K
authors.lastname: Uchida
authors.forename: H
authors.initials: H
authors.lastname: Hatakeyama
authors.forename: A
authors.initials: A
authors.lastname: Kurosawa
mesh_terms: D000818:Animals; D005990:Glycerol / Q000737:chemistry*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000633:toxicity; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011817:Rabbits; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D013449:Sulfonamides; D005990:Glycerol