A novel class of platelet activating factor (PAF) antagonists. II. Modification of the 2-position of the glycerol backbone of PAF-sulfonamide isosteres.
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.
Tsuri
T
T
Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Matsui
T
T
Haga
N
N
Kamata
S
S
Hagishita
S
S
Takahashi
K
K
Kakushi
H
H
Uchida
K
K
Hatakeyama
H
H
Kurosawa
A
A
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
D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D013449:Sulfonamides; D005990:Glycerol