Discovery of carmegliptin: A potent and long-acting dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes

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 enzy...

Full description

Saved in:

Bibliographic Details
Published in:	Bioorganic & medicinal chemistry letters Vol. 20; no. 3; pp. 1109 - 1113
Main Authors:	Mattei, Patrizio, Boehringer, Markus, Di Giorgio, Patrick, Fischer, Holger, Hennig, Michael, Huwyler, Joerg, Koçer, Buelent, Kuhn, Bernd, Loeffler, Bernd M., MacDonald, Alexander, Narquizian, Robert, Rauber, Etienne, Sebokova, Elena, Sprecher, Urs
Format:	Journal Article
Language:	English
Published:	Amsterdam Elsevier Ltd 01-02-2010 Elsevier
Subjects:	Animals Biological and medical sciences Clinical Trials, Phase II as Topic Crystallography, X-Ray Delayed-Action Preparations Diabetes Mellitus, Type 2 - drug therapy Diabetes Mellitus, Type 2 - enzymology Diabetes Mellitus, Type 2 - metabolism Dipeptidyl Peptidase 4 - metabolism Dipeptidyl peptidase-IV Dipeptidyl-Peptidase IV Inhibitors - administration & dosage Dipeptidyl-Peptidase IV Inhibitors - chemical synthesis Dipeptidyl-Peptidase IV Inhibitors - therapeutic use Dogs Drug Design General and cellular metabolism. Vitamins Glucagon-like peptide 1 Humans Hypoglycemic Agents - administration & dosage Hypoglycemic Agents - chemical synthesis Hypoglycemic Agents - therapeutic use Macaca fascicularis Medical sciences Mice Pharmacology. Drug treatments Quinolizines - administration & dosage Quinolizines - chemical synthesis Quinolizines - therapeutic use Rats Rats, Wistar Rats, Zucker Structure-based drug design Glucagon-like peptide 1 Structure-based drug design Dipeptidyl peptidase-IV Endocrinopathy Type 2 diabetes Rat Molecular structure Monkey Benzoquinolizine derivatives Hypoglycemic agent Gastrointestinal hormone Structure activity relation Primates Chemical synthesis Dipeptidyl-peptidase IV Long acting Enzyme Rodentia Enzyme inhibitor Metabolic diseases Inhibitor enzyme complex X ray diffraction Glucagon like peptide 1 Peptidases Vertebrata Mammalia Animal Hydrolases Dipeptidyl-peptidase IV inhibitor Pyrrolidone derivatives Fluorine Organic compounds Pharmacokinetics Carmegliptin Crystalline structure
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2009.12.024