Abstract
11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is the enzyme that converts cortisone to cortisol. Evidence suggests that selective inhibition of 11beta-HSD1 could treat diabetes and metabolic syndrome. Presented herein are the synthesis, structure-activity relationship, and in vivo evaluation of piperazine sulfonamides as 11beta-HSD1 inhibitors. Through modification of our initial lead 5a, we have identified potent and selective 11beta-HSD1 inhibitors such as 13q and 13u with good pharmacokinetic properties.
MeSH terms
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11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
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Administration, Oral
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Animals
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Biological Availability
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Cortisone / pharmacology
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Disease Models, Animal*
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Enzyme Inhibitors / administration & dosage
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / pharmacology*
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Enzyme Inhibitors / therapeutic use
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Hyperinsulinism / chemically induced
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Hyperinsulinism / drug therapy*
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Hyperinsulinism / enzymology
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Piperazines / administration & dosage
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Piperazines / pharmacokinetics
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Piperazines / pharmacology*
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Piperazines / therapeutic use
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Rats
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Sulfonamides / administration & dosage
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Sulfonamides / pharmacokinetics
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Sulfonamides / pharmacology*
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Sulfonamides / therapeutic use
Substances
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Enzyme Inhibitors
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Piperazines
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Sulfonamides
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11-beta-Hydroxysteroid Dehydrogenase Type 1
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Cortisone