title: The design and synthesis of indazole and pyrazolopyridine based glucokinase activators for the treatment of type 2 diabetes mellitus.
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.
authors.affiliation: Pfizer Cardiovascular, Metabolic and Endocrine Disease Research Unit, Pfizer Worldwide Research and Development, 620 Memorial Drive, Cambridge, MA 02139, USA. jeffrey.a.pfefferkorn@pfizer.com
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Pfefferkorn
authors.forename: Meihua
authors.initials: M
authors.lastname: Tu
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Filipski
authors.forename: Angel
authors.initials: A
authors.lastname: Guzman-Perez
authors.forename: Jianwei
authors.initials: J
authors.lastname: Bian
authors.forename: Gary E
authors.initials: GE
authors.lastname: Aspnes
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Sammons
authors.forename: Wei
authors.initials: W
authors.lastname: Song
authors.forename: Jian-Cheng
authors.initials: JC
authors.lastname: Li
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Jones
authors.forename: Leena
authors.initials: L
authors.lastname: Patel
authors.forename: Tim
authors.initials: T
authors.lastname: Rasmusson
authors.forename: Dongxiang
authors.initials: D
authors.lastname: Zeng
authors.forename: Kapil
authors.initials: K
authors.lastname: Karki
authors.forename: Michael
authors.initials: M
authors.lastname: Hamilton
authors.forename: Richard
authors.initials: R
authors.lastname: Hank
authors.forename: Karen
authors.initials: K
authors.lastname: Atkinson
authors.forename: John
authors.initials: J
authors.lastname: Litchfield
authors.forename: Robert
authors.initials: R
authors.lastname: Aiello
authors.forename: Levenia
authors.initials: L
authors.lastname: Baker
authors.forename: Nicole
authors.initials: N
authors.lastname: Barucci
authors.forename: Patricia
authors.initials: P
authors.lastname: Bourassa
authors.forename: Francis
authors.initials: F
authors.lastname: Bourbonais
authors.forename: Francis
authors.initials: F
authors.lastname: Bourbounais
authors.forename: Theresa
authors.initials: T
authors.lastname: D'Aquila
authors.forename: David R
authors.initials: DR
authors.lastname: Derksen
authors.forename: Margit
authors.initials: M
authors.lastname: MacDougall
authors.forename: Alan
authors.initials: A
authors.lastname: Robertson
mesh_terms: D000284:Administration, Oral; D000818:Animals; D045744:Cell Line, Tumor; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D015195:Drug Design; D005941:Glucokinase / Q000737:chemistry* / Q000378:metabolism; D005951:Glucose Tolerance Test; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D007328:Insulin / Q000378:metabolism; D007700:Kinetics; D011485:Protein Binding; D011719:Pyrazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011720:Pyrazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011725:Pyridines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: C579645:4-(6-(azetidine-1-carbonyl)-5-fluoropyridin-3-yloxy)-2-ethyl-N-(5-methylpyrazin-2-yl)-2H-indazole-6-carboxamide; D007004:Hypoglycemic Agents; D007191:Indazoles; D007328:Insulin; D011719:Pyrazines; D011720:Pyrazoles; D011725:Pyridines; C118531:pyrazolopyridine; D005941:Glucokinase