Heterocyclic ureas: inhibitors of acyl-CoA:cholesterol O-acyltransferase as hypocholesterolemic agents.
A series of diaryl-substituted heterocyclic ureas was prepared, and their ability to inhibit acyl-CoA: cholesterol O-acyltransferase (ACAT) in vitro and to lower plasma total cholesterol in cholesterol-fed animal models in vivo was examined. N-(2,6-Diisopropylphenyl)-N'-tetrazole or isoxazole-substituted heterocyclic ureas proved optimal. A carbon chain of 11-14 carbons substituted 1,3 with respect to the amine provided the optimal side chain. Substitution of the alkyl chain generally lowered activity. Tetrazole urea 2i dosed at 3 mg/kg lowered plasma total cholesterol (TC) 67% in an acute, cholesterol-fed (C-fed) rat model of hypercholesterolemia and 47% in C-fed dogs. Tetrazole 2i, dosed at 10 mg/kg, also lowered TC 52% and raised HDL cholesterol 113% in rats with pre-established hypercholesterolemia.
White
A D
AD
Department of Medicinal Chemistry, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
Creswell
M W
MW
Chucholowski
A W
AW
Blankley
C J
CJ
Wilson
M W
MW
Bousley
R F
RF
Essenburg
A D
AD
Hamelehle
K L
KL
Krause
B R
BR
Stanfield
R L
RL
Dominick
M A
MA
Neub
M
M
D000818:Animals; D000924:Anticholesteremic Agents / Q000737:chemistry*; D008076:Cholesterol, HDL / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D006937:Hypercholesterolemia / Q000188:drug therapy; D008297:Male; D051381:Rats; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D013777:Tetrazoles / Q000737:chemistry; D014508:Urea / Q000031:analogs & derivatives*
D000924:Anticholesteremic Agents; D008076:Cholesterol, HDL; D013777:Tetrazoles; D014508:Urea; D002785:Sterol O-Acyltransferase