Design, synthesis and structure-activity relationship studies of novel 4,4-bis(trifluoromethyl)imidazolines as acyl-CoA: cholesterol acyltransferase (ACAT) inhibitors and antihypercholesterolemic agents.
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.
Li
H Y
HY
The DuPont Merck Pharmaceutical Company, Experimental Station, Wilmington, DE 19880-0500, U.S.A. lihy@a1.lldmpc.umc.dupont.com
DeLucca
I
I
Boswell
G A
GA
Billheimer
J T
JT
Drummond
S
S
Gillies
P J
PJ
Robinson
C
C
D000924:Anticholesteremic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008968:Molecular Conformation; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D000924:Anticholesteremic Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D002785:Sterol O-Acyltransferase