Abstract
To combat the increased morbidity and mortality associated with the developing diabetes epidemic new therapeutic interventions are desirable. Inhibition of intracellular cortisol generation from cortisone by blocking 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) has been shown to ameliorate the risk factors associated with the metabolic syndrome. A challenge in developing 11β-HSD1 inhibitors has been the species selectivity of small molecules, as many compounds are primate specific. Here we describe our strategy to identify potent selective 11β-HSD1 inhibitors while ensuring target engagement in key metabolic tissues, liver and fat. This strategy enabled the identification of the clinical candidate, BI 135585.
Keywords:
11β-Hydroxysteroid dehydrogenase 1; Adipose tissue; Inhibitor; Liver; Type 2 diabetes.
Copyright © 2014 Elsevier B.V. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
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11-beta-Hydroxysteroid Dehydrogenase Type 1 / chemistry
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11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
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Animals
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Catalytic Domain
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Diabetes Mellitus, Type 2 / drug therapy*
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Diabetes Mellitus, Type 2 / enzymology
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Drug Evaluation, Preclinical
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Enzyme Inhibitors / therapeutic use
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Humans
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Macaca fascicularis
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Male
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Models, Molecular
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Oxazines / chemistry
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Oxazines / pharmacology*
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Oxazines / therapeutic use
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Pyridones / chemistry
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Pyridones / pharmacology*
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Pyridones / therapeutic use
Substances
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6-(2-hydroxy-2-methylpropyl)-3-(1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one
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Enzyme Inhibitors
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Oxazines
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Pyridones
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11-beta-Hydroxysteroid Dehydrogenase Type 1