Syntheses and biological evaluation of novel quinuclidine derivatives as squalene synthase inhibitors

• Published in: Bioorganic & medicinal chemistry 2003-05, Vol.11 (11), p.2403-2414
• Main Authors: Ishihara, Tsukasa, Kakuta, Hirotoshi, Moritani, Hiroshi, Ugawa, Tohru, Sakamoto, Shuichi, Tsukamoto, Shin-ichi, Yanagisawa, Isao
• Format: Article
• Language: English
• Subjects: Animals; Anticholesteremic Agents - chemical synthesis; Anticholesteremic Agents - pharmacology; Biological and medical sciences; Cholesterol - blood; Cricetinae; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Farnesyl-Diphosphate Farnesyltransferase - antagonists & inhibitors; Farnesyl-Diphosphate Farnesyltransferase - metabolism; Fluorenes - chemical synthesis; Fluorenes - pharmacology; General and cellular metabolism. Vitamins; Humans; Inhibitory Concentration 50; Medical sciences; Microsomes, Liver - metabolism; Pharmacology. Drug treatments; Quinuclidines - chemical synthesis; Quinuclidines - pharmacology; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(03)00143-3

Squalene synthase (E.C. 2.5.1.21) catalyses the reductive dimerization of two molecules of farnesyl diphosphate to form squalene and is involved in the first committed step in cholesterol biosynthesis. Inhibition of this enzyme is therefore an attractive target for hypocholesterolemic strategies. A series of quinuclidine derivatives incorporating a tricyclic system was synthesized and evaluated for their ability to inhibit squalene synthase in vitro. A 9 H-fluorene moiety was found to be optimal as the tricyclic system for potent inhibitory activity. Improved activity can be achieved with a conformationally constrained three-atom linkage connecting the tricyclic system with the quinuclidine nucleus. Among these compounds, ( Z)-3-[2-(9 H-fluoren-2-yloxy)ethylidene]-quinuclidine hydrochloride 31 was found to be a potent inhibitor of squalene synthase derived from hamster liver and human hepatoma cells with IC 50 values of 76 and 48 nM, respectively. Oral dosing of compound 31 demonstrated effective reduction of plasma non-HDL cholesterol levels in hamsters. Novel quinuclidine derivatives incorporating a tricyclic system were synthesized and evaluated for inhibitory activities against squalene synthase. ( Z)-3-Ethylidenequinuclidine derivative 31 exhibited the most potent inhibitory activity and significantly reduced non-HDL cholesterol levels in hamsters following oral dosing.