Literature DB >> 27437083

Novel Series of Potent Glucokinase Activators Leading to the Discovery of AM-2394.

Paul J Dransfield1, Vatee Pattaropong1, Sujen Lai1, Zice Fu1, Todd J Kohn1, Xiaohui Du1, Alan Cheng1, Yumei Xiong1, Renee Komorowski2, Lixia Jin1, Marion Conn1, Eric Tien2, Walter E DeWolf3, Ronald J Hinklin3, Thomas D Aicher3, Christopher F Kraser3, Steven A Boyd3, Walter C Voegtli3, Kevin R Condroski3, Murielle Veniant-Ellison2, Julio C Medina1, Jonathan Houze1, Peter Coward1.   

Abstract

Glucokinase (GK) catalyzes the phosphorylation of glucose to glucose-6-phosphate. We present the structure-activity relationships leading to the discovery of AM-2394, a structurally distinct GKA. AM-2394 activates GK with an EC50 of 60 nM, increases the affinity of GK for glucose by approximately 10-fold, exhibits moderate clearance and good oral bioavailability in multiple animal models, and lowers glucose excursion following an oral glucose tolerance test in an ob/ob mouse model of diabetes.

Entities:  

Keywords:  AM-2394; GKA; Glucokinase activator

Year:  2016        PMID： 27437083      PMCID： PMC4948016          DOI： 10.1021/acsmedchemlett.6b00140

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  11 in total

1.  Identification of a new class of glucokinase activators through structure-based design.

Authors:  Ronald J Hinklin; Steven A Boyd; Mark J Chicarelli; Kevin R Condroski; Walter E DeWolf; Patrice A Lee; Waiman Lee; Ajay Singh; Laurie Thomas; Walter C Voegtli; Lance Williams; Thomas D Aicher
Journal:  J Med Chem       Date:  2013-09-25       Impact factor: 7.446

2.  Piragliatin (RO4389620), a novel glucokinase activator, lowers plasma glucose both in the postabsorptive state and after a glucose challenge in patients with type 2 diabetes mellitus: a mechanistic study.

Authors:  Riccardo C Bonadonna; Tim Heise; Christophe Arbet-Engels; Christoph Kapitza; Angelo Avogaro; Joe Grimsby; Jay Zhi; Joseph F Grippo; Raffaella Balena
Journal:  J Clin Endocrinol Metab       Date:  2010-08-25       Impact factor: 5.958

Review 3.  Glucokinase as glucose sensor and metabolic signal generator in pancreatic beta-cells and hepatocytes.

Authors:  F M Matschinsky
Journal:  Diabetes       Date:  1990-06       Impact factor: 9.461

4.  Allosteric activators of glucokinase: potential role in diabetes therapy.

Authors:  Joseph Grimsby; Ramakanth Sarabu; Wendy L Corbett; Nancy-Ellen Haynes; Fred T Bizzarro; John W Coffey; Kevin R Guertin; Darryl W Hilliard; Robert F Kester; Paige E Mahaney; Linda Marcus; Lida Qi; Cheryl L Spence; John Tengi; Mark A Magnuson; Chang An Chu; Mark T Dvorozniak; Franz M Matschinsky; Joseph F Grippo
Journal:  Science       Date:  2003-07-18       Impact factor: 47.728

Review 5.  Assessing the potential of glucokinase activators in diabetes therapy.

Authors:  Franz M Matschinsky
Journal:  Nat Rev Drug Discov       Date:  2009-04-17       Impact factor: 84.694

6.  Discovery of 2-pyridylureas as glucokinase activators.

Authors:  Ronald J Hinklin; Thomas D Aicher; Deborah A Anderson; Brian R Baer; Steven A Boyd; Kevin R Condroski; Walter E DeWolf; Christopher F Kraser; Maralee McVean; Susan P Rhodes; Hillary L Sturgis; Walter C Voegtli; Lance Williams; Jonathan B Houze
Journal:  J Med Chem       Date:  2014-09-17       Impact factor: 7.446

7.  Effects of MK-0941, a novel glucokinase activator, on glycemic control in insulin-treated patients with type 2 diabetes.

Authors:  Gary E Meininger; Russell Scott; Maria Alba; Yue Shentu; Edmund Luo; Himal Amin; Michael J Davies; Keith D Kaufman; Barry J Goldstein
Journal:  Diabetes Care       Date:  2011-10-12       Impact factor: 19.112

Review 8.  Present status of clinical deployment of glucokinase activators.

Authors:  Akinobu Nakamura; Yasuo Terauchi
Journal:  J Diabetes Investig       Date:  2014-11-10       Impact factor: 4.232

Review 9.  Molecular physiology of mammalian glucokinase.

Authors:  P B Iynedjian
Journal:  Cell Mol Life Sci       Date:  2009-01       Impact factor: 9.261

10.  Characterization of a novel glucokinase activator in rat and mouse models.

Authors:  Min Lu; Pingping Li; Gautam Bandyopadhyay; William Lagakos; Walter E Dewolf; Taylor Alford; Mark Joseph Chicarelli; Lance Williams; Deborah A Anderson; Brian R Baer; Maralee McVean; Marion Conn; Murielle M Véniant; Peter Coward
Journal:  PLoS One       Date:  2014-02-12       Impact factor: 3.240
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  2 in total

1.  A practically simple, catalyst free and scalable synthesis of N-substituted ureas in water.

Authors:  Lata Tiwari; Varun Kumar; Bhuvesh Kumar; Dinesh Mahajan
Journal:  RSC Adv       Date:  2018-06-13       Impact factor: 4.036

2.  5-Alkyl-2-urea-Substituted Pyridines: Identification of Efficacious Glucokinase Activators with Improved Properties.

Authors:  Todd J Kohn; Xiaohui Du; SuJen Lai; YuMei Xiong; Renee Komorowski; Murielle Veniant; Zice Fu; Xianyun Jiao; Vatee Pattaropong; David Chow; Mario Cardozo; Lixia Jin; Marion Conn; Walter E DeWolf; Christopher F Kraser; Ronald J Hinklin; Mark L Boys; Julio C Medina; Jonathan Houze; Paul Dransfield; Peter Coward
Journal:  ACS Med Chem Lett       Date:  2016-06-01       Impact factor: 4.345
  2 in total

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