Inhibitors of acyl-CoA: cholesterol O-acyltransferase (ACAT). Part 1: Identification and structure-activity relationships of a novel series of substituted N-alkyl-N-biphenylylmethyl-N′-arylureas

• Published in: Bioorganic & medicinal chemistry 1998, Vol.6 (1), p.15-30
• Main Authors: Tanaka, Akira, Terasawa, Takeshi, Hagihara, Hiroyuki, Sakuma, Yuri, Ishibe, Noriko, Sawada, Masae, Takasugi, Hisashi, Tanaka, Hirokazu
• Format: Article
• Language: English
• Subjects: Anilides - pharmacokinetics; Anilides - pharmacology; Animals; Biological Availability; Biphenyl Compounds - chemistry; Biphenyl Compounds - pharmacology; Cholesterol - blood; Cholesterol, Dietary - administration & dosage; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - pharmacology; In Vitro Techniques; Intestinal Mucosa - enzymology; Male; Methylurea Compounds - chemical synthesis; Methylurea Compounds - pharmacokinetics; Methylurea Compounds - pharmacology; Microsomes - enzymology; Phenylurea Compounds - chemical synthesis; Phenylurea Compounds - chemistry; Phenylurea Compounds - pharmacokinetics; Phenylurea Compounds - pharmacology; Pyridines - pharmacokinetics; Pyridines - pharmacology; Rabbits; Rats; Rats, Sprague-Dawley; Sterol O-Acyltransferase - antagonists & inhibitors; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(97)10009-8

A series of N-alkyl- N-biphenylylmethyl- N′-arylurea and related derivatives represented by 1 have been prepared and evaluated for their ability to inhibit acyl-CoA: cholesterol O-acyltransferase in vitro and to lower plasma cholesterol levels in cholesterol-fed rats in vivo. Linking of two phenyl groups via oxygen and introduction of fluorine at appropriate positions on the biphenyl moiety improved in vitro and in vivo activity. From this series of analogs, compound 40 (FR179254), which had potent in vitro potency (rabbit intestinal microsomes IC 50 = 25 nM), showed excellent plasma cholesterol-lowering activity when administered via the diet (ED 50 = 0.045 mg/kg). However, the hypocholesterolemic effect of this compound was moderate when dosed by oral gavage in PEG400 as a vehicle (ED 50 = 5.3 mg/kg). Modification of the N′-aryl moiety led to the identification of compound 50 (FR182980) which was efficicious in both dosing models (ED 50 = 0.034 mg/kg and 0.11 mg/kg, respectively. The synthesis and biological evaluation of a novel series of ACAT inhibitors are reported.