Synthesis and biological evaluations of quinoline-based HMG-CoA reductase inhibitors

Citation
M. Suzuki et al., Synthesis and biological evaluations of quinoline-based HMG-CoA reductase inhibitors, BIO MED CH, 9(10), 2001, pp. 2727-2743
Citations number
47
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Chemistry & Analysis
Journal title
BIOORGANIC & MEDICINAL CHEMISTRY
ISSN journal
0968-0896 → ACNP
Volume
9
Issue
10
Year of publication
2001
Pages
2727 - 2743
Database
ISI
SICI code
0968-0896(200110)9:10<2727:SABEOQ>2.0.ZU;2-G
Abstract
A series of quinoline-based 3,5-dihydroxyheptenoic acid derivatives were sy nthesized from quinolinecarboxylic acid esters by homologation, aldol conde nsation with ethyl acetoacetate dianion, and reduction of 3-hydroxyketone t o evaluate their ability to inhibit the enzyme HMG-CoA reductase in vitro. In agreement with previous literature, a strict structural requirement exis ts on the external ring, and 4-fluorophenyl is the most active in this syst em. For the central ring, substitution on positions 6, 7, and 8 of the cent ral quinoline nucleus moderately affected the potency, whereas the alkyl si de chain on the 2-position had a more pronounced influence on activity. Amo ng the derivatives, NK-104 (pitavastatin calcium), which has a cyclopropyl group as the alkyl side chain, showed the greatest potency. We found that f urther modulation and improvement in potency at inhibiting HMG-CoA reductas e was obtained by having the optimal substituents flanking the desmethyline valonic acid portion, that is, 4-fluorophenyl and cyclopropyl, instead of t he usual isopropyl group. (C) 2001 Elsevier Science Ltd, All rights reserve d.