Cozzi P, Branzoli U, Lovisolo P P, Orsini G, Carganico G, Pillan A, Chiari A
J Med Chem. 1986 Mar;29(3):404-10. doi: 10.1021/jm00153a016.
A series of 3-(1-imidazolyl)chroman-4-ones and 2-(1-imidazolyl)-1-tetralones II, some of their alcohols, and some related compounds were synthesized and tested for hypolipidemic activity. Compounds II, bearing appropriate lipophilic substituents on the phenyl ring, strongly reduced total serum cholesterol while raising high-density lipoprotein cholesterol in diet-induced hypercholesterolemic rats. 3-(1-Imidazolyl)chroman-4-ols and 2-(1-imidazolyl)-1-tetralols corresponding to II retained the hypolipidemic activity while removal of the carbonyl or hydroxy group adjacent to imidazole gave inactive compounds. Although many of the active compounds significantly increased liver weight, the one studied as a model, 6-chloro-3-(1-imidazolyl)-2,3-dihydro-4H-1-benzopyran-4-one (5), caused no peroxisome proliferation. Compound 5 and the corresponding alcohol 40, as representatives of the ketone and alcohol series, showed significant hypolipidemic activity in normolipemic rats. Some of the compounds assayed in cholesterol biosynthesis inhibited acetate incorporation but none inhibited HMG-CoA reductase. 5-Bromo-6-hydroxy-2-(1-imidazolyl)-3,4-dihydro-1(2H)-naphthalenone (38), which showed strong activity but caused little hepatomegaly in the rat, was chosen for further pharmacological evaluation.
合成了一系列3-(1-咪唑基)色满-4-酮和2-(1-咪唑基)-1-萘满酮II、它们的一些醇类以及一些相关化合物，并对其进行了降血脂活性测试。在饮食诱导的高胆固醇血症大鼠中，在苯环上带有适当亲脂性取代基的化合物II能显著降低血清总胆固醇，同时提高高密度脂蛋白胆固醇水平。与II对应的3-(1-咪唑基)色满-4-醇和2-(1-咪唑基)-1-萘满醇保留了降血脂活性，而去除咪唑相邻的羰基或羟基则得到无活性的化合物。尽管许多活性化合物显著增加了肝脏重量，但作为模型研究的6-氯-3-(1-咪唑基)-2,3-二氢-4H-1-苯并吡喃-4-酮(5)并未引起过氧化物酶体增殖。化合物5和相应的醇40作为酮类和醇类系列的代表，在正常血脂大鼠中显示出显著的降血脂活性。一些在胆固醇生物合成中测定的化合物抑制了乙酸盐的掺入，但没有一种抑制HMG-CoA还原酶。选择在大鼠中显示出强活性但几乎不引起肝肿大的5-溴-6-羟基-2-(1-咪唑基)-3,4-二氢-1(2H)-萘满酮(38)进行进一步的药理学评价。
