Tsuri T, Matsui T, Haga N, Kamata S, Hagishita S, Takahashi K, Kakushi H, Uchida K, Hatakeyama H, Kurosawa A
Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Chem Pharm Bull (Tokyo). 1992 Jan;40(1):85-95. doi: 10.1248/cpb.40.85.
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.
为了持续努力获得更有效的血小板活化因子（PAF）拮抗剂，我们尝试合成一系列PAF-磺酰胺电子等排体，其中2-位的取代基被修饰为除甲氧基之外的乙酰氧基类似物。这些修饰产生了高活性的PAF拮抗剂。化合物3-[2-(5-甲基-2H-四唑-2-基)-3-(十八烷基氨甲酰氧基)丙基氨基磺酰基]丙基喹啉碘化物（52）在体外对富含兔血小板血浆中PAF诱导的血小板聚集的抑制作用（IC50 = 125 nM）以及在体内对PAF诱导的小鼠致死性的保护作用方面表现出最有效的活性，且作用持续时间延长。合成了该化合物的旋光活性对映体，发现（S）-（-）-异构体（IC50 = 87 nM）的效力是（R）-（+）-异构体（IC50 = 289 nM）的三倍，清楚地例证了这种新型化合物PAF拮抗剂作用中的对映选择性。
