1. Discovery of carmegliptin: A potent and long-acting dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes
- Author
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Patrizio Mattei, Joerg Huwyler, Patrick Di Giorgio, Buelent Kocer, Robert Narquizian, Etienne Rauber, Bernd Michael Loeffler, Alexander Macdonald, Michael Hennig, Elena Sebokova, Markus Boehringer, Holger Fischer, Bernd Kuhn, and Urs Sprecher
- Subjects
Dipeptidyl Peptidase 4 ,Clinical Biochemistry ,Pharmaceutical Science ,Type 2 diabetes ,Crystallography, X-Ray ,Biochemistry ,Chemical synthesis ,Dipeptidyl peptidase ,Mice ,Clinical Trials, Phase II as Topic ,Dogs ,Diabetes mellitus ,Drug Discovery ,Hydrolase ,medicine ,Animals ,Humans ,Hypoglycemic Agents ,Rats, Wistar ,Molecular Biology ,chemistry.chemical_classification ,Dipeptidyl-Peptidase IV Inhibitors ,biology ,Organic Chemistry ,medicine.disease ,Glucagon-like peptide-1 ,Rats ,Rats, Zucker ,Macaca fascicularis ,Enzyme ,Diabetes Mellitus, Type 2 ,chemistry ,Enzyme inhibitor ,Delayed-Action Preparations ,Drug Design ,biology.protein ,Molecular Medicine ,Quinolizines - Abstract
Design, synthesis, and SAR are described for a class of DPP-IV inhibitors based on aminobenzo[a]quinolizines with non-aromatic substituents in the S1 specificity pocket. One representative thereof, carmegliptin (8p), was chosen for clinical development. Its X-ray structure in complex with the enzyme and early efficacy data in animal models of type 2 diabetes are also presented.
- Published
- 2010
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