Abstract
Selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) have considerable potential as treatments for type 2 diabetes. Presented herein are the syntheses, structure-activity relationships, and efficacy evaluation of 4-(phenylsulfonamidomethyl)benzamides as 11beta-HSD1 inhibitors. Through modification of our initial lead 5, we have identified potent and selective 11beta-HSD1 inhibitors, such as 11n, which demonstrated improved glycemic control, decreased serum lipids, and enhanced insulin sensitivity when dosed ip in diabetic ob/ob mice.
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 / metabolism*
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Animals
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Benzamides / chemical synthesis*
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Benzamides / pharmacology
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Blood Glucose / metabolism
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Diabetes Mellitus, Experimental / metabolism
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Diabetes Mellitus, Type 2 / drug therapy*
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Diabetes Mellitus, Type 2 / metabolism
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Drug Discovery
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Humans
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Hydrolysis
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Inhibitory Concentration 50
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Mice
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Mice, Obese
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Models, Chemical
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis*
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Sulfonamides / pharmacology
Substances
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Benzamides
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Blood Glucose
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Sulfonamides
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benzamide
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11-beta-Hydroxysteroid Dehydrogenase Type 1