Designing glucokinase activators with reduced hypoglycemia risk: discovery of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide as a clinical candidate for the treatment of type 2 diabetes mellitus

Jeffrey A. Pfefferkorn; Angel Guzman-Perez; Peter J. Oates; John Litchfield; Gary Aspnes; Arindrajit Basak; John Benbow; Martin A. Berliner; Jianwei Bian; Chulho Choi; Kevin Freeman-Cook; Jeffrey W. Corbett; Mary Didiuk; Joshua R. Dunetz; Kevin J. Filipski; William M. Hungerford; Christopher S. Jones; Kapil Karki; Anthony Ling; Jian-Cheng Li; Leena Patel; Christian Perreault; Hud Risley; James Saenz; Wei Song; Meihua Tu; Robert Aiello; Karen Atkinson; Nicole Barucci; David Beebe; Patricia Bourassa; Francis Bourbounais; Anne M. Brodeur; Rena Burbey; Jing Chen; Theresa D'Aquila; David R. Derksen; Nahor Haddish-Berhane; Cong Huang; James Landro; Amanda Lee Lapworth; Margit MacDougall; David Perregaux; John Pettersen; Alan Robertson; Beijing Tan; Judith L. Treadway; Shenping Liu; Xiayang Qiu; John Knafels; Mark Ammirati; Xi Song; Paul DaSilva-Jardine; Spiros Liras; Laurel Sweet; Timothy P. Rolph

doi:10.1039/C1MD00116G

Designing glucokinase activators with reduced hypoglycemia risk: discovery of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide as a clinical candidate for the treatment of type 2 diabetes mellitus†

Jeffrey A. Pfefferkorn,*^a Angel Guzman-Perez,^a Peter J. Oates,^a John Litchfield,^a Gary Aspnes,^a Arindrajit Basak,^a John Benbow,^a Martin A. Berliner,^a Jianwei Bian,^a Chulho Choi,^a Kevin Freeman-Cook,^a Jeffrey W. Corbett,^a Mary Didiuk,^a Joshua R. Dunetz,^a Kevin J. Filipski,^a William M. Hungerford,^a Christopher S. Jones,^a Kapil Karki,^a Anthony Ling,^a Jian-Cheng Li,^a Leena Patel,^a Christian Perreault,^a Hud Risley,^a James Saenz,^a Wei Song,^a Meihua Tu,^a Robert Aiello,^a Karen Atkinson,^a Nicole Barucci,^a David Beebe,^a Patricia Bourassa,^a Francis Bourbounais,^a Anne M. Brodeur,^a Rena Burbey,^a Jing Chen,^a Theresa D'Aquila,^a David R. Derksen,^a Nahor Haddish-Berhane,^a Cong Huang,^a James Landro,^a Amanda Lee Lapworth,^a Margit MacDougall,^a David Perregaux,^a John Pettersen,^a Alan Robertson,^a Beijing Tan,^a Judith L. Treadway,^a Shenping Liu,^a Xiayang Qiu,^a John Knafels,^a Mark Ammirati,^a Xi Song,^a Paul DaSilva-Jardine,^a Spiros Liras,^a Laurel Sweet^a and Timothy P. Rolph^a

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* Corresponding authors

^a Pfizer Worldwide Research & Development, Eastern Point Road, Groton, CT
E-mail: jeffrey.a.pfefferkorn@pfizer.com
Tel: +860 686 3421

Abstract

Glucokinase is a key regulator of glucose homeostasis and small molecule activators of this enzyme represent a promising opportunity for the treatment of Type 2 diabetes. Several glucokinase activators have advanced to clinical studies and demonstrated promising efficacy; however, many of these early candidates also revealed hypoglycemia as a key risk. In an effort to mitigate this hypoglycemia risk while maintaining the promising efficacy of this mechanism, we have investigated a series of substituted 2-methylbenzofurans as “partial activators” of the glucokinase enzyme leading to the identification of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide as an early development candidate.

MedChemComm

Designing glucokinase activators with reduced hypoglycemia risk: discovery of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide as a clinical candidate for the treatment of type 2 diabetes mellitus†

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Designing glucokinase activators with reduced hypoglycemia risk: discovery of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide as a clinical candidate for the treatment of type 2 diabetes mellitus

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