Literature DB >> 25516785

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

Xiaohui Du1, Ronald J Hinklin2, Yumei Xiong1, Paul Dransfield1, Jaehyeon Park1, Todd J Kohn1, Vatee Pattaropong1, SuJen Lai1, Zice Fu1, Xianyun Jiao1, David Chow1, Lixia Jin1, Jasmine Davda1, Murielle M Veniant3, Deborah A Anderson2, Brian R Baer2, Josef R Bencsik2, Steven A Boyd2, Mark Joseph Chicarelli2, Peter J Mohr2, Bin Wang2, Kevin R Condroski2, Walter E DeWolf2, Marion Conn1, Thanhvien Tran1, Jerry Yang1, Thomas D Aicher2, Julio C Medina1, Peter Coward1, Jonathan B Houze1.   

Abstract

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.

Entities:  

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

Year:  2014        PMID： 25516785      PMCID： PMC4265826          DOI： 10.1021/ml500341w

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


  18 in total

1.  A protein from rat liver confers to glucokinase the property of being antagonistically regulated by fructose 6-phosphate and fructose 1-phosphate.

Authors:  E Van Schaftingen
Journal:  Eur J Biochem       Date:  1989-01-15

2.  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

3.  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 4.  Novel glucokinase activators: a patent review (2008 - 2010).

Authors:  Ramakanth Sarabu; Steven J Berthel; Robert F Kester; Jefferson W Tilley
Journal:  Expert Opin Ther Pat       Date:  2010-12-15       Impact factor: 6.674

Review 5.  Glucokinase activators for the potential treatment of type 2 diabetes.

Authors:  J Grimsby; S J Berthel; R Sarabu
Journal:  Curr Top Med Chem       Date:  2008       Impact factor: 3.295

6.  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 7.  Strategies for the design of hepatoselective glucokinase activators to treat type 2 diabetes.

Authors:  Jeffrey A Pfefferkorn
Journal:  Expert Opin Drug Discov       Date:  2013-01-06       Impact factor: 6.098

Review 8.  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

9.  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

Review 10.  National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2·7 million participants.

Authors:  Goodarz Danaei; Mariel M Finucane; Yuan Lu; Gitanjali M Singh; Melanie J Cowan; Christopher J Paciorek; John K Lin; Farshad Farzadfar; Young-Ho Khang; Gretchen A Stevens; Mayuree Rao; Mohammed K Ali; Leanne M Riley; Carolyn A Robinson; Majid Ezzati
Journal:  Lancet       Date:  2011-06-24       Impact factor: 79.321
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  2 in total

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

Authors:  Paul J Dransfield; Vatee Pattaropong; Sujen Lai; Zice Fu; Todd J Kohn; Xiaohui Du; Alan Cheng; Yumei Xiong; Renee Komorowski; Lixia Jin; Marion Conn; Eric Tien; Walter E DeWolf; Ronald J Hinklin; Thomas D Aicher; Christopher F Kraser; Steven A Boyd; Walter C Voegtli; Kevin R Condroski; Murielle Veniant-Ellison; Julio C Medina; Jonathan Houze; Peter Coward
Journal:  ACS Med Chem Lett       Date:  2016-05-23       Impact factor: 4.345

Review 2.  Cyclobutanes in Small-Molecule Drug Candidates.

Authors:  Marnix R van der Kolk; Mathilde A C H Janssen; Floris P J T Rutjes; Daniel Blanco-Ania
Journal:  ChemMedChem       Date:  2022-03-29       Impact factor: 3.540
  2 in total

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