Traxler P, Kump W, Mueller K, Tosch W
Pharmaceuticals Research Laboratories, Ciba-Geigy, Ltd., Basle, Switzerland.
J Med Chem. 1990 Feb;33(2):552-60. doi: 10.1021/jm00164a013.
Series of 3-piperidinyl- and 3-piperazinylrifamycins and to a certain extent 3-hydrazonorifamycins all bearing lipophilic side chains were found to exert potent hypolipidemic activity in lowering both serum cholesterol and LDL-cholesterol in rats. Starting from 3-[N'-(2,4,6-trimethylbenzyl)-N-piperazinyl]rifamycin SV (compound 25), a series of derivatives were synthesized with the aim of dissociating the hypolipidemic from the antibacterial activity, leading to the 8-O,N-dipivaloyl derivative of 25 (compound 48), which is devoid of any antibacterial activity but shows about 50-60% reduction of LDL-cholesterol and 20-30% reduction of serum cholesterol at a dose of 10 mg/kg. Compound 48 was selected for further pharmacological evaluation.
研究发现，一系列带有亲脂性侧链的3-哌啶基和3-哌嗪基利福霉素，以及在一定程度上的3-腙基利福霉素，在降低大鼠血清胆固醇和低密度脂蛋白胆固醇方面具有强大的降血脂活性。从3-[N'-(2,4,6-三甲基苄基)-N-哌嗪基]利福霉素SV（化合物25）开始，合成了一系列衍生物，目的是将降血脂活性与抗菌活性分离，得到25的8-O,N-二新戊酰基衍生物（化合物48），该衍生物没有任何抗菌活性，但在10mg/kg的剂量下，低密度脂蛋白胆固醇降低约50-60%，血清胆固醇降低20-30%。选择化合物48进行进一步的药理评价。
