Heterocyclic amides: inhibitors of acyl-CoA:cholesterol O-acyl transferase with hypocholesterolemic activity in several species and antiatherosclerotic activity in the rabbit.
A series of heterocyclic amides were synthesized and evaluated as inhibitors of acyl-CoA: cholesterol O-acyltransferase (ACAT) in vitro and for cholesterol lowering in cholesterol-fed rats. Compounds were evaluated for cell-based macrophage ACAT inhibition, bioactivity, and adrenal toxicity. Candidates were selected for evaluation in cholesterol-fed dogs and, ultimately, the injured cholesterol-fed rabbit model of atherosclerosis. The heterocyclic amides potently inhibited rabbit liver ACAT (IC50's = 0.014-0.11 microM), and the majority of compounds significantly lowered plasma cholesterol (42-68%) in an acute cholesterol-fed rat model at 3 mg/kg. The most efficacious compounds in the rat were evaluated for bioactivity in vivo and arterial ACAT inhibition in a cell-based macrophage ACAT assay. Two highly bioactive analogs, (+/-)-2-(3-dodecylisoxazol-5-yl)-2-phenyl-N-(2,4,6-trimethoxypheny l) acetamide (13a) and (+/-)-2-(5-dodecylisoxazol-3-yl)-2-phenyl-N-(2,4,6-trimethoxypheny l) acetamide (16a), were selected for further study and were found to be nontoxic in a guinea pig model of adrenal toxicity. Compounds 13a and 16a lowered total cholesterol in the cholesterol-fed rat, rabbit, and dog models of pre-established hypercholesterolemia. Compound 13a in the injured cholesterol-fed rabbit model of atherosclerosis was effective in slowing the development of cholesteryl ester-rich thoracic aortic lesions, reducing lesion coverage by 53% at a dose of 1 mg/kg.
White
A D
AD
Department of Medicinal Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
Purchase
C F
CF
Picard
J A
JA
Anderson
M K
MK
Mueller
S B
SB
Bocan
T M
TM
Bousley
R F
RF
Hamelehle
K L
KL
Krause
B R
BR
Lee
P
P
Stanfield
R L
RL
Reindel
J F
JF
D000081:Acetamides / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D000307:Adrenal Gland Diseases / Q000139:chemically induced; D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D001161:Arteriosclerosis / Q000188:drug therapy*; D002784:Cholesterol / Q000097:blood; D004285:Dogs; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000627:therapeutic use; D006168:Guinea Pigs; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D008099:Liver / Q000201:enzymology; D008297:Male; D015394:Molecular Structure; D011817:Rabbits; D051381:Rats; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*
C101723:2-(3-dodecylisoxazol-5-yl)-2-phenyl-N-(2,4,6-trimethoxyphenyl)acetamide; C101724:2-(5-dodecylisoxazol-3-yl)-2-phenyl-N-(2,4,6-trimethoxyphenyl)acetamide; D000081:Acetamides; D000924:Anticholesteremic Agents; D004791:Enzyme Inhibitors; D007555:Isoxazoles; D002784:Cholesterol; D002785:Sterol O-Acyltransferase