Sliskovic D R, Picard J A, O'Brien P M, Liao P, Roark W H, Roth B D, Anderson M A, Mueller S B, Bocan T M, Bousley R F, Hamelehle K L, Homan R, Reindel J F, Stanfield R L, Turluck D, Krause B R
Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
J Med Chem. 1998 Feb 26;41(5):682-90. doi: 10.1021/jm970560h.
We prepared a series of alpha-substituted malonester amides that were evaluated for their ability to inhibit acyl-CoA:cholesterol O-acyl transferase activity in vitro and to lower plasma total cholesterol levels in a variety of cholesterol-fed animal models. Compounds of this series were also useful in examining the relationship between adrenal toxicity and ACAT inhibition. One compound from this series, 9f, was a potent inhibitor of ACAT in both the microsomal and cellular assays. It was also bioavailable as determined by both a bioassay and a HPLC-UV assay. This compound was evaluated in both guinea pig and dog models of adrenal toxicity and compared to tetrazole amide 15. In the most sensitive species, the dog, both of these compounds achieved good plasma levels; however, compound 9f caused adrenal necrosis, whereas compound 15 had no effect on the adrenal gland. This adds to the growing body of evidence that the adrenal toxicity observed with ACAT inhibitors may not be mechanism related.
我们制备了一系列α-取代的丙二酸酯酰胺，并对其在体外抑制酰基辅酶A：胆固醇O-酰基转移酶活性以及在多种高胆固醇喂养动物模型中降低血浆总胆固醇水平的能力进行了评估。该系列化合物在研究肾上腺毒性与ACAT抑制之间的关系方面也很有用。该系列中的一种化合物9f，在微粒体和细胞试验中都是ACAT的有效抑制剂。通过生物测定和HPLC-UV测定确定它也具有生物利用度。该化合物在豚鼠和狗的肾上腺毒性模型中进行了评估，并与四唑酰胺15进行了比较。在最敏感的物种狗中，这两种化合物都达到了良好的血浆水平；然而，化合物9f导致肾上腺坏死，而化合物15对肾上腺没有影响。这增加了越来越多的证据表明，ACAT抑制剂观察到的肾上腺毒性可能与机制无关。
