| Autor: |
Fouchet MH; Department of Medicinal chemistry, Laboratoire GlaxoSmithKline, 25-27 Avenue du Québec, 91951 Les Ulis, France. marie-helene.fouchet@gsk.com, Donche F, Martin C, Bouillot A, Junot C, Boullay AB, Potvain F, Magny SD, Coste H, Walker M, Issandou M, Dodic N |
| Jazyk: |
angličtina |
| Zdroj: |
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2008 Jun 01; Vol. 16 (11), pp. 6218-32. Date of Electronic Publication: 2008 Apr 18. |
| DOI: |
10.1016/j.bmc.2008.04.034 |
| Abstrakt: |
We describe the discovery of novel potent inhibitors of 2,3-oxidosqualene:lanosterol cyclase inhibitors (OSCi) from a focused pharmacophore-based screen. Optimization of the most tractable hits gave a series of compounds showing inhibition of cholesterol biosynthesis at 2mg/kg in the rat with distinct pharmacokinetic profiles. Two compounds were selected for toxicological study in the rat for 21 days in order to test the hypothesis that low systemic exposure could be used as a strategy to avoid the ocular side effects previously described with OSCi. We demonstrate that for this series of inhibitors, a reduction of systemic exposure is not sufficient to circumvent cataract liabilities. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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