alpha-Substituted malonester amides: tools to define the relationship between ACAT inhibition and adrenal toxicity

D R Sliskovic; J A Picard; P M O'Brien; P Liao; W H Roark; B D Roth; M A Anderson; S B Mueller; T M Bocan; R F Bousley; K L Hamelehle; R Homan; J F Reindel; R L Stanfield; D Turluck; B R Krause

doi:10.1021/jm970560h

alpha-Substituted malonester amides: tools to define the relationship between ACAT inhibition and adrenal toxicity

J Med Chem. 1998 Feb 26;41(5):682-90. doi: 10.1021/jm970560h.

Authors

D R Sliskovic¹, J A Picard, P M O'Brien, P Liao, W H Roark, B D Roth, M A Anderson, S B Mueller, T M Bocan, R F Bousley, K L Hamelehle, R Homan, J F Reindel, R L Stanfield, D Turluck, B R Krause

Affiliation

¹ Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.

PMID: 9513596
DOI: 10.1021/jm970560h

Abstract

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.

Publication types

Comparative Study

MeSH terms

Adrenal Glands / drug effects*
Adrenal Glands / pathology*
Amides / pharmacology
Amides / toxicity
Animals
Anticholesteremic Agents / chemical synthesis
Biological Availability
Cholesterol / blood
Cholesterol, Dietary / administration & dosage
Chromatography, High Pressure Liquid
Dogs
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / pharmacology*
Enzyme Inhibitors / toxicity*
Female
Guinea Pigs
Male
Malonates / chemical synthesis
Malonates / pharmacology*
Malonates / toxicity*
Mice
Microsomes, Liver / enzymology
Necrosis
Phenylacetates / chemical synthesis
Phenylacetates / pharmacology*
Phenylacetates / toxicity*
Rats
Rats, Sprague-Dawley
Sterol O-Acyltransferase / antagonists & inhibitors*
Tetrazoles / pharmacology
Tetrazoles / toxicity

Substances

Amides
Anticholesteremic Agents
Cholesterol, Dietary
Enzyme Inhibitors
Malonates
Phenylacetates
Tetrazoles
alpha-(((2,6-bis(1-methylethyl)phenyl)amino)carbonyl)benzeneacetic acid dodecyl ester
Cholesterol
Sterol O-Acyltransferase