The design and synthesis of indazole and pyrazolopyridine based glucokinase activators for the treatment of Type 2 diabetes mellitus

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...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2012-12, Vol.22 (23), p.7100-7105
Hauptverfasser:	Pfefferkorn, Jeffrey A., Tu, Meihua, Filipski, Kevin J., Guzman-Perez, Angel, Bian, Jianwei, Aspnes, Gary E., Sammons, Matthew F., Song, Wei, Li, Jian-Cheng, Jones, Christopher S., Patel, Leena, Rasmusson, Tim, Zeng, Dongxiang, Karki, Kapil, Hamilton, Michael, Hank, Richard, Atkinson, Karen, Litchfield, John, Aiello, Robert, Baker, Levenia, Barucci, Nicole, Bourassa, Patricia, Bourbounais, Francis, D’Aquila, Theresa, Derksen, David R., MacDougall, Margit, Robertson, Alan
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral Animals Biological and medical sciences Cell Line, Tumor chemistry Diabetes mellitus Diabetes Mellitus, Type 2 - drug therapy Drug Design General and cellular metabolism. Vitamins Glucokinase Glucokinase - chemistry Glucokinase - metabolism Glucokinase activator Glucose Tolerance Test Half-Life Humans Hypoglycemic Agents - chemical synthesis Hypoglycemic Agents - pharmacokinetics Hypoglycemic Agents - therapeutic use Indazoles - chemical synthesis Indazoles - chemistry Indazoles - pharmacokinetics Indazoles - therapeutic use Insulin - metabolism Kinetics Medical sciences noninsulin-dependent diabetes mellitus patients Pharmacokinetics Pharmacology. Drug treatments Protein Binding Pyrazines - chemical synthesis Pyrazines - pharmacokinetics Pyrazines - therapeutic use Pyrazoles - chemistry Pyrazoles - pharmacokinetics Pyrazoles - therapeutic use Pyridines - chemistry Pyridines - pharmacokinetics Pyridines - therapeutic use Rats Rats, Sprague-Dawley Structure-Activity Relationship Type 2 diabetes mellitus
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Zusammenfassung:	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.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2012.09.082