| Autor: |
Sliskovic DR; Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105, USA., Picard JA, O'Brien PM, Liao P, Roark WH, Roth BD, Anderson MA, Mueller SB, Bocan TM, Bousley RF, Hamelehle KL, Homan R, Reindel JF, Stanfield RL, Turluck D, Krause BR |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 1998 Feb 26; Vol. 41 (5), pp. 682-90. |
| DOI: |
10.1021/jm970560h |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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