ACAT inhibitors derived from hetero-Diels-Alder cycloadducts of thioaldehydes.
Acyl-CoA:cholesterol acyltransferase (ACAT) is the enzyme largely responsible for intracellular cholesterol esterification. A systemic inhibitor of ACAT is believed to be able to slow or even reverse the atherosclerotic process. Towards that goal, a series of cyclic sulfides, derived from the hetero-Diels-Alder reaction of thioaldehydes with 1,3-dienes, and bearing carboxamide substituents, were prepared and evaluated for in vitro (in several tissues and species) and ex vivo ACAT inhibition. Minor changes in subsequent structure were found to have a significant effect in optimization of the biological activity of this series of compounds.
DuPont Merck Pharmaceutical Company, DuPont Experimental Station, Wilmington, DE 19880-0500, USA.
R G
RG
Wilde
J T
JT
Billheimer
S J
SJ
Germain
E A
EA
Hausner
P C
PC
Meunier
D A
DA
Munzer
J K
JK
Stoltenborg
P J
PJ
Gillies
D L
DL
Burcham
S M
SM
Huang
J D
JD
Klaczkiewicz
S S
SS
Ko
R R
RR
Wexler
D000447:Aldehydes / Q000737:chemistry*; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000737:chemistry*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D013438:Sulfhydryl Compounds / Q000737:chemistry*
D000447:Aldehydes; D004791:Enzyme Inhibitors; D013438:Sulfhydryl Compounds; D002785:Sterol O-Acyltransferase