Novel Acyl-CoA:Cholesterol Acyltransferase Inhibitors. Synthesis and Biological Activity of 3-Quinolylurea Derivatives

• Published in: Journal of medicinal chemistry 1994-06, Vol.37 (13), p.2079-2084
• Main Authors: Tawada, Hiroyuki, Harcourt, Myles, Kawamura, Noriaki, Kajino, Masahiro, Ishikawa, Eiichiro, Sugiyama, Yasuo, Ikeda, Hitoshi, Meguro, Kanji
• Format: Article
• Language: English
• Subjects: Animals; Anticholesteremic Agents - chemical synthesis; Anticholesteremic Agents - pharmacology; Anticholesteremic Agents - therapeutic use; Chemistry; Cholesterol - blood; Exact sciences and technology; Gastric Mucosa - drug effects; Gastric Mucosa - enzymology; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Male; Organic chemistry; Phenylurea Compounds - chemical synthesis; Phenylurea Compounds - chemistry; Phenylurea Compounds - pharmacology; Preparations and properties; Rats; Rats, Sprague-Dawley; Sterol O-Acyltransferase - antagonists & inhibitors; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00039a020

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.