Abstract
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.
MeSH terms
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Animals
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Anticholesteremic Agents / adverse effects
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Anticholesteremic Agents / chemical synthesis
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Anticholesteremic Agents / pharmacokinetics
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Cataract / chemically induced
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Cataract / drug therapy
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Cataract / enzymology*
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Cell Line, Tumor
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Dyslipidemias / chemically induced
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Dyslipidemias / enzymology*
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Enzyme Inhibitors / adverse effects
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / pharmacokinetics*
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Eye / drug effects*
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Eye / metabolism
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Female
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Humans
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Intramolecular Transferases / antagonists & inhibitors*
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Liver / drug effects
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Liver / metabolism
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Male
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Oxazoles / pharmacokinetics
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Oxazoles / therapeutic use
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Piperazines / adverse effects
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Piperazines / chemical synthesis
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Piperazines / pharmacokinetics
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Piperidines / pharmacokinetics
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Piperidines / therapeutic use
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Rats
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Rats, Sprague-Dawley
Substances
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Anticholesteremic Agents
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Enzyme Inhibitors
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Oxazoles
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Piperazines
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Piperidines
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BIBB 515
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Intramolecular Transferases
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lanosterol synthase