Inhibitors of acyl-CoA:cholesterol O-acyltransferase. 17. Structure-activity relationships of several series of compounds derived from N-chlorosulfonyl isocyanate.
Several series of acyl-CoA:cholesterol O-acyltransferase inhibitors were prepared by the stepwise addition of nitrogen, oxygen, and sulfur nucleophiles to N-chlorosulfonyl isocyanate. The (aminosulfonyl)ureas 3-44 were the most potent inhibitors in vitro, with several compounds having IC50 values < 1 microM. Although the other series of compounds were not as potent in vitro, many compounds did display good in vivo activity in cholesterol-fed rats. Several of the oxysulfonyl carbamates (including CI-999, 115) showed excellent lipid-lowering activity in the chronic in vivo screen, demonstrating significant cholesterol lowering in a pre-established hypercholesterolemic state.
Picard
J A
JA
Department of Medicinal Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
O'Brien
P M
PM
Sliskovic
D R
DR
Anderson
M K
MK
Bousley
R F
RF
Hamelehle
K L
KL
Krause
B R
BR
Stanfield
R L
RL
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D017953:Isocyanates / Q000494:pharmacology*; D051381:Rats; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D017953:Isocyanates; C041875:N-chlorosulfonyl isocyanate; D002785:Sterol O-Acyltransferase