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Issue 9, 2011
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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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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.

Graphical abstract: 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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Publication details

The article was received on 04 May 2011, accepted on 07 Jun 2011 and first published on 05 Jul 2011


Article type: Concise Article
DOI: 10.1039/C1MD00116G
Citation: Med. Chem. Commun., 2011,2, 828-839

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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

    J. A. Pfefferkorn, A. Guzman-Perez, P. J. Oates, J. Litchfield, G. Aspnes, A. Basak, J. Benbow, M. A. Berliner, J. Bian, C. Choi, K. Freeman-Cook, J. W. Corbett, M. Didiuk, J. R. Dunetz, K. J. Filipski, W. M. Hungerford, C. S. Jones, K. Karki, A. Ling, J. Li, L. Patel, C. Perreault, H. Risley, J. Saenz, W. Song, M. Tu, R. Aiello, K. Atkinson, N. Barucci, D. Beebe, P. Bourassa, F. Bourbounais, A. M. Brodeur, R. Burbey, J. Chen, T. D'Aquila, D. R. Derksen, N. Haddish-Berhane, C. Huang, J. Landro, A. Lee Lapworth, M. MacDougall, D. Perregaux, J. Pettersen, A. Robertson, B. Tan, J. L. Treadway, S. Liu, X. Qiu, J. Knafels, M. Ammirati, X. Song, P. DaSilva-Jardine, S. Liras, L. Sweet and T. P. Rolph, Med. Chem. Commun., 2011, 2, 828
    DOI: 10.1039/C1MD00116G

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