Novel acyl-CoA:cholesterol acyltransferase inhibitors. Synthesis and biological activity of 3-quinolylurea derivatives.
A series of 3-quinolylurea derivatives (1) was synthesized and evaluated for acyl-CoA:cholesterol acyltransferase (ACAT) inhibitory activity. For in vitro studies, the most potent inhibitory activity was found in derivatives having substituents at the 6,7- or 6,8-positions and an ortho-substituted phenyl group at the 4-position of quinoline ring. The 2,4-difluorophenyl group appeared to be the optimum N'-substituent of the urea moiety. The IC50 values of compounds 52-54 and 59 were in the nanomolar order. Plasma cholesterol-lowering activity of compounds 50, 52, and 54 was observed at less than 1 mg/kg/day in cholesterol-fed rats. Compound 52 was also hypocholesterolemic in hamsters fed a diet without loading cholesterol.
Tawada
H
H
Pharmaceutical Research Laboratories II, Takeda Chemical Industries, Ltd., Osaka, Japan.
Harcourt
M
M
Kawamura
N
N
Kajino
M
M
Ishikawa
E
E
Sugiyama
Y
Y
Ikeda
H
H
Meguro
K
K
D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D002784:Cholesterol / Q000097:blood*; D005753:Gastric Mucosa / Q000187:drug effects / Q000201:enzymology; D008297:Male; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D000924:Anticholesteremic Agents; D010671:Phenylurea Compounds; C088280:N-(4-(2-chlorophenyl)-6,7-dimethyl-3-quinolyl)-N'-(2,4-difluorophenyl)urea; D002784:Cholesterol; D002785:Sterol O-Acyltransferase