New β-Alanine Derivatives Are Orally Available Glucagon Receptor Antagonists
| Autor: | Lars Ynddal, Ulla G. Sidelmann, Christian K. Sams, Peter Madsen, Carsten Behrens, Lotte Bjerre Knudsen, Behrend F. Lundt, Jesper Lau, Shengua Shi, Christian L. Brand, Anthony Lai Ling, Lone Pridal, Plewe Michael Bruno, Dan Kiel |
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| Rok vydání: | 2007 |
| Předmět: |
endocrine system
medicine.medical_specialty Administration Oral Biological Availability Mice Obese Peptide hormone Glucagon Diabetes Mellitus Experimental Mice Structure-Activity Relationship Dogs Oral administration Internal medicine Drug Discovery Receptors Glucagon medicine Animals Humans Hypoglycemic Agents Receptor IC50 Pancreatic hormone Chemistry Antagonist Rats Endocrinology Diabetes Mellitus Type 2 beta-Alanine Molecular Medicine Glucagon receptor hormones hormone substitutes and hormone antagonists |
| Zdroj: | Journal of Medicinal Chemistry. 50:113-128 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm058026u |
| Popis: | A weak human glucagon receptor antagonist with an IC50 of 7 microM 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. |
| Databáze: | OpenAIRE |
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