C5-Alkyl-2-methylurea-Substituted Pyridines as a New Class of Glucokinase Activators

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• 作者：Xiaohui Du ; Ronald J. Hinklin ; Yumei Xiong ; Paul Dransfield ; Jaehyeon Park ; Todd J. Kohn ; Vatee Pattaropong ; SuJen Lai ; Zice Fu ; Xianyun Jiao ; David Chow ; Lixia Jin ; Jasmine Davda ; Murielle M. Veniant ; Deborah A. Anderson ; Brian R. Baer ; Josef R. Bencsik ; Steven A. Boyd ; Mark Joseph Chicarelli ; Peter J. Mohr ; Bin Wang ; Kevin R. Condroski ; Walter E. DeWolf ; Marion Conn ; Thanhvien Tran ; Jerry Yang ; Thomas D. Aicher ; Julio C. Medina ; Peter Coward ; Jonathan B. Houze
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2014
• 出版时间：December 11, 2014
• 年：2014
• 卷：5
• 期：12
• 页码：1284-1289
• 全文大小：400K
• ISSN：1948-5875

文摘

Glucokinase (GK) activators represent a class of type 2 diabetes therapeutics actively pursued due to the central role that GK plays in regulating glucose homeostasis. Herein we report a novel C5-alkyl-2-methylurea-substituted pyridine series of GK activators derived from our previously reported thiazolylamino pyridine series. Our efforts in optimizing potency, enzyme kinetic properties, and metabolic stability led to the identification of compound 26 (AM-9514). This analogue showed a favorable combination of in vitro potency, enzyme kinetic properties, acceptable pharmacokinetic profiles in preclinical species, and robust efficacy in a rodent PD model.

Keywords:

Type 2 diabetes; glucokinase activator; GKA; methyl urea-substituted pyridines