Lawrence W H, Howell R D, Gollamudi R
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee-Memphis 38163.
J Pharm Sci. 1994 Feb;83(2):222-5. doi: 10.1002/jps.2600830222.
A group of nipecotamides (3-carbamoylpiperidines) were designed, synthesized, and evaluated for their ability to protect platelets from induced aggregation. An in vivo mouse thrombosis model was used to determine the protection afforded by these compounds from sudden thrombotic death induced by intravenous collagen plus epinephrine. Enantioselectivity appears to play a pivotal role in determining the activity of these compounds. Lipophilicity, whereas previously found to correlate well with in vitro activity, did not directly influence in vivo activity. The presence of an amide function on the 3-position of the piperidine ring was essential for activity. Of the 10 compounds reported here, alpha,alpha'-bis[3-(N-benzyl-N-methylcarbamoyl)-piperidino]-p-xyle ne dihydrobromide (4) was the most potent in preventing induced intravascular platelet aggregation in mice, with a 50% effective dose of (ED50) of 27.5 mumol (20 mg)/kg.
设计、合成了一组氮杂环丁酰胺（3-氨基甲酰基哌啶），并评估了它们保护血小板免受诱导聚集的能力。使用体内小鼠血栓形成模型来确定这些化合物对静脉注射胶原蛋白加肾上腺素诱导的突然血栓性死亡的保护作用。对映选择性似乎在决定这些化合物的活性中起关键作用。亲脂性虽然先前发现与体外活性密切相关，但并未直接影响体内活性。哌啶环3位上存在酰胺官能团对活性至关重要。在此报道的10种化合物中，α,α'-双[3-(N-苄基-N-甲基氨基甲酰基)-哌啶基]-对二甲苯二氢溴化物（4）在预防小鼠体内诱导的血管内血小板聚集方面最有效，50%有效剂量（ED50）为27.5 μmol（20 mg）/kg。
