Journal ArticleDOI
Design and evaluation of a novel series of 2,3-oxidosqualene cyclase inhibitors with low systemic exposure, relationship between pharmacokinetic properties and ocular toxicity
Marie-Hélène Fouchet,Frédéric Donche,Christelle Martin,Anne Marie Jeanne Bouillot,Christophe Junot,Anne-Benedicte Boullay,Florent Potvain,Sylvie Demaria Magny,Hervé Coste,M Walker,Marc Issandou,Nerina Dodic +11 more
TLDR
It is demonstrated that for this series of inhibitors, a reduction of systemic exposure is not sufficient to circumvent cataract liabilities.About:
This article is published in Bioorganic & Medicinal Chemistry.The article was published on 2008-06-01. It has received 15 citations till now. The article focuses on the topics: Lanosterol synthase.read more
Citations
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Journal ArticleDOI
Regulation and deregulation of cholesterol homeostasis: The liver as a metabolic “power station”
TL;DR: An updated overview of liver cholesterol metabolism regulation and deregulation and the causes of cholesterol metabolism-related diseases is provided and current pharmacological treatment and novel hypocholesterolemic strategies will be introduced.
Journal ArticleDOI
Potential role of nonstatin cholesterol lowering agents
TL;DR: The structure–function relationships of FDFT1, SQLE, and OSC are reviewed highlighting the advantages that the downstream inhibition of HMGR could provide when compared to the statin‐based therapy.
Journal ArticleDOI
Compound Prioritization Methods Increase Rates of Chemical Probe Discovery in Model Organisms
Iain M. Wallace,Malene L. Urbanus,Genna M. Luciani,Andrew R. Burns,Mitchell K. L. Han,Hao Wang,Kriti Arora,Lawrence E. Heisler,Michael Proctor,Robert P. St.Onge,Terry Roemer,Peter J. Roy,Carolyn L. Cummins,Gary D. Bader,Corey Nislow,Guri Giaever +15 more
TL;DR: Empirical and in silico application of the model enriched the discovery of bioactive compounds in diverse model organisms and identified specific inhibitors of lanosterol synthase and of stearoyl-CoA 9-desaturase that inhibit yeast growth.
Journal ArticleDOI
Novel pyrrole- and 1,2,3-triazole-based 2,3-oxidosqualene cyclase inhibitors.
TL;DR: Amide derivatives of 8 and 12 preserved the inhibitory activity of parent compound 3, which provided a reasonable starting point for further structure-activity-relationship (SAR) studies on related compounds.
Journal ArticleDOI
Small molecules, both dietary and endogenous, influence the onset of lens cataracts.
Stephen Barnes,Roy A. Quinlan +1 more
TL;DR: The role of small molecules in the prevention or causation of cataracts is examined, including those associated with diet, metabolic pathways and drug therapy (steroids).
References
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Journal ArticleDOI
Lovastatin and beyond: the history of the HMG-CoA reductase inhibitors.
TL;DR: The discovery and development of lovastatin — the first approved inhibitor of HMG-CoA reductase — and the clinical trials that have provided the evidence for the ability of drugs in this class to reduce the morbidity and mortality associated with cardiovascular disease are described.
Journal ArticleDOI
Insight into steroid scaffold formation from the structure of human oxidosqualene cyclase
Ralf Thoma,Tanja Schulz-Gasch,Brigitte D'Arcy,Jörg Benz,Johannes Aebi,Henrietta Dehmlow,Michael Hennig,Martine Stihle,Armin Ruf +8 more
TL;DR: The target protein with an inhibitor that showed cholesterol lowering in vivo opens the way for the structure-based design of new OSC inhibitors, and the complex with the reaction product lanosterol gives a clear picture of the way in which the enzyme achieves product specificity in this highly exothermic cyclization reaction.
Journal ArticleDOI
Pharmacotherapy for dyslipidaemia – current therapies and future agents
Harold Bays,Evan A. Stein +1 more
TL;DR: Current lipid-altering agents that lower low density lipoprotein cholesterol (LDL-C) primarily through increased hepatic LDL receptor activity include statins, bile acid sequestrants/resins and cholesterol absorption inhibitors, as well as nutraceuticals such as oat bran, psyllium and soy proteins.
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Ro 48-8.071, a new 2,3-oxidosqualene:lanosterol cyclase inhibitor lowering plasma cholesterol in hamsters, squirrel monkeys, and minipigs: comparison to simvastatin.
Olivier Morand,Johannes Aebi,Henrietta Dehmlow,Yu-Hua Ji,N Gains,Hans Lengsfeld,Jacques Himber +6 more
TL;DR: Findings clearly differentiate the OSC inhibitor Ro 48-8.071 from simvastatin, and support the view that OSC is a distinct key component in the regulation of the cholesterol synthesis pathway.
Journal ArticleDOI
Cholesterol and cataracts
TL;DR: Results of clinical trials of 1-5 years duration in older patient populations indicate high ocular safety, but considering the slow life-long growth of the lens and its continuing need for cholesterol, longterm safety of the vastatins should perhaps be viewed in units of 10 or 20 years, particularly with younger patients.