Acyl CoA:cholesterol acyltransferase (ACAT) inhibitors: synthesis and structure-activity relationship studies of a new series of trisubstituted imidazoles.
A series of 4,5-diaryl-2-(substituted thio)-1H-imidazoles has been synthesized and demonstrated to be potent inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). The design, synthesis, and structure-activity relationships for this series are reported herein. One of the compounds from this series, N'-(2,4-difluorophenyl)-N-[5-[(4,5-diaryl-1H-imidazol-2- yl)thio]pentyl]-N-heptylurea (DuP 128), was selected for development as an intestinally active ACAT inhibitor. DuP 128 is a potent ACAT inhibitor in vitro and in vivo, inhibiting ACAT in rat hepatic microsomes with an IC50 = 10 nM and possessing potent antihypercholesterolemic activity in vivo.
Higley
C A
CA
DuPont Merck Research Laboratories, Wilmington, Delaware 19880-0402.
Wilde
R G
RG
Maduskuie
T P
TP
Johnson
A L
AL
Pennev
P
P
Billheimer
J T
JT
Robinson
C S
CS
Gillies
P J
PJ
Wexler
R R
RR
D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002784:Cholesterol / Q000097:blood; D006224:Cricetinae; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D008647:Mesocricetus; D008862:Microsomes, Liver / Q000201:enzymology; D015394:Molecular Structure; D051381:Rats; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
D000924:Anticholesteremic Agents; D007093:Imidazoles; D014508:Urea; D002784:Cholesterol; C084073:lecimibide; D002785:Sterol O-Acyltransferase