Inhibitors of acyl-CoA:cholesterol O-acyltransferase. 11. Structure-activity relationships of several series of compounds derived from N-(chlorocarbonyl) isocyanate.
Five series of compounds (4-9) derived from N-(chlorocarbonyl) isocyanate have been synthesized and evaluated for their ability to inhibit the enzyme acyl-CoA:cholesterol O-acyltransferase and lower plasma cholesterol levels in cholesterol-fed rats. Structure-activity relationships indicate that the imino dicarboxylates (6 and 7) and the oxycarbonyl thiocarbamates (8) are the most potent and efficacious series. In these series, the combination of a 2,6-diisopropylphenyl group and an aliphatic alkyl group with a chain length between 6 and 14 carbon atoms gives good activity in vitro and in vivo. In addition, a hydrogen donor is required to maintain good in vitro activity, and the acidic proton on the central nitrogen in these series appears to be important for in vivo activity.
Picard
J A
JA
Department of Medicinal Chemistry, parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105.
Bousley
R F
RF
Lee
H T
HT
Hamelehle
K L
KL
Krause
B R
BR
Minton
L L
LL
Sliskovic
D R
DR
Stanfield
R L
RL
D000818:Animals; D002784:Cholesterol / Q000097:blood; D000960:Hypolipidemic Agents / Q000737:chemistry / Q000494:pharmacology*; D017953:Isocyanates / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D000960:Hypolipidemic Agents; D017953:Isocyanates; D002784:Cholesterol; D002785:Sterol O-Acyltransferase