Abstract
Glucokinase activators represent a promising potential treatment for patients with Type 2 diabetes. Herein, we report the identification and optimization of a series of novel indazole and pyrazolopyridine based activators leading to the identification of 4-(6-(azetidine-1-carbonyl)-5-fluoropyridin-3-yloxy)-2-ethyl-N-(5-methylpyrazin-2-yl)-2H-indazole-6-carboxamide (42) as a potent activator with favorable preclinical pharmacokinetic properties and in vivo efficacy.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Administration, Oral
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Animals
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Cell Line, Tumor
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Diabetes Mellitus, Type 2 / drug therapy
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Drug Design*
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Glucokinase / chemistry*
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Glucokinase / metabolism
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Glucose Tolerance Test
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Half-Life
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Humans
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Hypoglycemic Agents / chemical synthesis*
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Hypoglycemic Agents / pharmacokinetics
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Hypoglycemic Agents / therapeutic use
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Indazoles / chemical synthesis
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Indazoles / chemistry*
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Indazoles / pharmacokinetics
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Indazoles / therapeutic use
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Insulin / metabolism
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Kinetics
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Protein Binding
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Pyrazines / chemical synthesis*
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Pyrazines / pharmacokinetics
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Pyrazines / therapeutic use
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Pyrazoles / chemistry*
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Pyrazoles / pharmacokinetics
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Pyrazoles / therapeutic use
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Pyridines / chemistry*
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Pyridines / pharmacokinetics
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Pyridines / therapeutic use
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Rats
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Rats, Sprague-Dawley
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Structure-Activity Relationship
Substances
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4-(6-(azetidine-1-carbonyl)-5-fluoropyridin-3-yloxy)-2-ethyl-N-(5-methylpyrazin-2-yl)-2H-indazole-6-carboxamide
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Hypoglycemic Agents
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Indazoles
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Insulin
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Pyrazines
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Pyrazoles
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Pyridines
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pyrazolopyridine
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Glucokinase