307989-61-3Relevant academic research and scientific papers
Novel glucagon receptor antagonists with improved selectivity over the glucose-dependent insulinotropic polypeptide receptor
Kodra, János T.,J?rgensen, Anker Steen,Andersen, Birgitte,Behrens, Carsten,Brand, Christian Lehn,Christensen, Inger Th?ger,Guldbrandt, Mette,Jeppesen, Claus Bekker,Knudsen, Lotte B.,Madsen, Peter,Nishimura, Erica,Sams, Christian,Sidelmann, Ulla G.,Pedersen, Raymon A.,Lynn, Francis C.,Lau, Jesper
supporting information; experimental part, p. 5387 - 5396 (2009/07/01)
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.
New β-alanine derivatives are orally available glucagon receptor antagonists
Lau, Jesper,Behrens, Garsten,Sidelmann, Ulla G.,Knudsen, Lotte B.,Lundt, Behrend,Sams, Christian,Ynddal, Lars,Brand, Christian L.,Pridal, Lone,Ling, Anthony,Kiel, Dan,Plewe, Michael,Shi, Shengua,Madsen, Peter
, p. 113 - 128 (2007/10/03)
A weak human glucagon receptor antagonist with an IC50 of 7 μM was initially found by screening of libraries originally targeted to mimic the binding of the glucagon-like peptide (GLP-1) hormone to its receptor. Optimization of this hit for binding affinity for the glucagon receptor led to ligands with affinity in the nanomolar range. In addition to receptor binding, optimization efforts were made to stabilize the molecules against fast metabolic turnover. A potent antagonist of the human human glucagon receptor was obtained that had 17% oral availability in rats with a plasma half-life of 90 min. The major metabolites of this lead were identified and used to further optimize this series with respect to pharmacokinetic properties. This final optimization led to a potent glucagon antagonist that was orally available in rats and dogs and was efficacious in lowering blood glucose levels in a diabetic animal model.
Glucagon antagonists/inverse agonists
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, (2008/06/13)
Disclosed is a novel class of compounds of formula (I) wherein V, A, Y, Z, R1, E, X and D are as defined in the specification. These compounds act to antagonize the action of the glucagon hormone on the glucagon receptor. Owing to their antagonizing effect of the glucagon receptor, the compounds are suitable for treating or preventing glucagon-mediated conditions and diseases such as hyperglycemia, Type 1 diabetes, Type 2 diabetes and obesity.
