Syntheses and biological evaluation of novel quinuclidine derivatives as squalene synthase inhibitors.
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 9H-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-(9H-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.
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21Miyukigaoka, Tsukuba, 305-8585, Ibaraki, Japan. ishhat@yamanouchi.co.jp
Tsukasa
T
Ishihara
Hirotoshi
H
Kakuta
Hiroshi
H
Moritani
Tohru
T
Ugawa
Shuichi
S
Sakamoto
Shin-ichi
S
Tsukamoto
Isao
I
Yanagisawa
D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002784:Cholesterol / Q000097:blood; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005449:Fluorenes / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008862:Microsomes, Liver / Q000378:metabolism; D011812:Quinuclidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000924:Anticholesteremic Agents; D004791:Enzyme Inhibitors; D005449:Fluorenes; D011812:Quinuclidines; D002784:Cholesterol; D013186:Farnesyl-Diphosphate Farnesyltransferase