Novel Glucagon Receptor Antagonists with Improved Selectivity over the Glucose-Dependent Insulinotropic Polypeptide Receptor

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• 作者：Já ; nos T. Kodra ; Anker Steen J&#248 ; rgensen ; Birgitte Andersen ; Carsten Behrens ; Christian Lehn Brand ; Inger Th&#248 ; ger Christensen ; Mette Guldbrandt ; Claus Bekker Jeppesen ; Lotte B. Knudsen ; Pe
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：September 11, 2008
• 年：2008
• 卷：51
• 期：17
• 页码：5387-5396
• 全文大小：211K
• 年卷期：v.51,no.17(September 11, 2008)
• ISSN：1520-4804

文摘

Optimization of a new series of small molecule human glucagon receptor (hGluR) antagonists is described. In the process of optimizing glucagon receptor antagonists, we counter-screened against the closely related human gastric inhibitory polypeptide receptor (hGIPR), and through structure activity analysis, we obtained compounds with low nanomolar affinities toward the hGluR, which were selective against the hGIPR and the human glucagon-like peptide-1 receptor (hGLP-1R). In the best cases, we obtained a >50 fold selectivity for the hGluR over the hGIPR and a >1000 fold selectivity over the hGLP-1R. A potent and selective glucagon receptor antagonist was demonstrated to inhibit glucagon-induced glycogenolysis in primary rat hepatocytes as well as to lower glucagon-induced hyperglycemia in Sprague−Dawley rats. Furthermore, the compound was shown to lower blood glucose in the ob/ob mouse after oral dosing.