Abstract
A series of benzamide derivatives were assembled by using the privileged-fragment-merging (PFM) strategy and their SAR studies as glucokinase activators were described. Compounds 5 and 16b were identified having a suitable balance of potency and activation profile. They showed EC(50) values of 28.3 and 44.8 nM, and activation folds of 2.4 and 2.2, respectively. However, both compounds displayed a minor reduction in plasma glucose levels on imprinting control region (ICR) mice. Unfavorable pharmacokinetic profiles (PK) were also observed on these two compounds.
Copyright © 2012 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Benzamides / blood
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Benzamides / chemical synthesis*
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Benzamides / chemistry*
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Benzamides / pharmacokinetics
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Benzamides / pharmacology*
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Biological Availability
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Drug Design*
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Enzyme Activation / drug effects
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Glucokinase / chemistry
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Glucokinase / metabolism*
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Hypoglycemic Agents / blood
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Hypoglycemic Agents / chemical synthesis*
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Hypoglycemic Agents / pharmacokinetics
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Hypoglycemic Agents / pharmacology*
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Mice
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Mice, Inbred ICR
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Structure-Activity Relationship
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Thiazoles / blood
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Thiazoles / chemical synthesis*
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Thiazoles / chemistry
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Thiazoles / pharmacokinetics
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Thiazoles / pharmacology
Substances
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(S)-3-(4-((3-fluoropyrrolidin-1-yl)sulfonyl)phenoxy)-5-((3-methylbut-2-en-1-yl)oxy)-N-(thiazol-2-yl)benzamide
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3-(4-(cyclopropylsulfonyl)phenoxy)-5-((3-methylbut-2-en-1-yl)oxy)-N-(thiazol-2-yl)benzamide
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Benzamides
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Hypoglycemic Agents
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Thiazoles
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benzamide
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Glucokinase