吡咯类HMG-CoA还原酶抑制剂的合成及生物活性

Synthesis and biological evaluation of condensed pyrrole-based HMG-CoA reductase inhibitors

目的:设计并合成吡咯类HMG-CoA还原酶抑制剂并测定其对HMG-CoA还原酶的抑制活性。方法:根据他汀类药物的构效关系,设计了一类(3R,5R)-7-[2-(4-氟苯基)-3-芳基-4-芳氨甲酰基-5-环丙基-1-吡咯基]-3,5-二羟基庚酸钠化合物(Ia～Im),通过测定烟酰胺腺嘌呤二核苷酸磷酸(NADPH)的降低速率,得到化合物对HMG-CoA还原酶的抑制活性。结果与结论:设计并合成了未见文献报道的HMG-CoA还原酶抑制剂13个,目标化合物结构经IR、1HNMR和HR-ESIMS确证。对所有化合物进行了HMG-CoA还原酶抑制活性测试,有5个化合物有抑制活性,其中化合物Ie的抑制活性与阳性对照药阿托伐他汀相当。

Aim： To design, synthesize the condensed pyrrole-based HMG-CoA reductase inhibitors, and evaluate their inhibitory activities on HMG-CoA-reductase. Methods： A series of （3R, 5R）-7-（3-aryl-4-arylaminocarbonyl-5- cyclopropyl-2-（4-fluorophenyl） pyrrole-l-yl） -3, 5-dihydroxylheptanoic acid sodium were designed based on the SAR of HMG-CoA reductase inhibitors （Ia - Ira）. The designed compounds were synthesized and their inhibitory activities on HMG-CoA-reductase were investigated by determining the reduction rate of NADPH. Results and Conclusion： Thirteen new compounds were obtained by the approach and their structures were confirmed by IR, ^1H NMR and HR-ESIMS. It was found that five target compounds possessed HMG-CoA reductase inhibitory activities and that the inhibitory activity of compound Ie was similar to that of atorvastatin used as a positive control.