ABSTRACT
Novel 4,4-bis(trifluoromethyl)imidazolines have been found to be the potent acyl-CoA cholesterol acyltransferase (ACAT) inhibitors. ACAT is responsible for cholesterol esterification in the intestine, liver, and the arterial wall. These novel imidazolines also inhibit cholesterol ester formation in the macrophage. Several compounds have shown potent serum cholesterol-lowering activity in several animal models. Para-substitution of the 2-phenyl is critical for in vitro and in vivo activity. The 4,4-bis(trifluoromethyl)imidazolines with a para-cyano group on 2-phenyl and a 4-alkylcyclohexyl amide as the side-chain at the 5-position possess the most potent inhibitory activity in this series. Based on biochemical studies, this series acts as a competitive inhibitor with respect to cholesterol binding at the enzyme, which distinguishes it from most of the ACAT inhibitors discovered to date. Preliminary biological studies supported by X-ray crystal structures, molecular modeling, and structure-activity relationship (SAR) studies suggest that this series may be a cholesterol mimic.
Subject(s)
Anticholesteremic Agents/chemical synthesis , Anticholesteremic Agents/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Sterol O-Acyltransferase/antagonists & inhibitors , Anticholesteremic Agents/chemistry , Enzyme Inhibitors/chemistry , Imidazoles/chemistry , Molecular Conformation , Structure-Activity RelationshipABSTRACT
A series of N,N'-disubstituted cyclic urea 3-benzamides has been synthesized and evaluated for HIV protease inhibition and antiviral activity. Some of these benzamides have been shown to be potent inhibitors of HIV protease with Ki < 0.050 nM and IC90 < 20 nM for viral replication and, as such, may be useful in the treatment of AIDS. The synthesis and quantitative structure-activity relationship for this benzamide series will be discussed.
