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.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidase IV Inhibitors , Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Drug Design , Hypoglycemic Agents/chemical synthesis , Quinolizines/chemical synthesis , Animals , Clinical Trials, Phase II as Topic , Crystallography, X-Ray , Delayed-Action Preparations , Diabetes Mellitus, Type 2/enzymology , Diabetes Mellitus, Type 2/metabolism , Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/administration & dosage , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Dogs , Humans , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/therapeutic use , Macaca fascicularis , Mice , Quinolizines/administration & dosage , Quinolizines/therapeutic use , Rats , Rats, Wistar , Rats, ZuckerABSTRACT
Synthesis and SAR are described for a structurally distinct class of DPP-IV inhibitors based on aminobenzo[a]quinolizines bearing (hetero-)aromatic substituents in the S1 specificity pocket. The m-(fluoromethyl)-phenyl derivative (S,S,S)-2g possesses the best fit in the S1 pocket. However, (S,S,S)-2i, bearing a more hydrophilic 5-methyl-pyridin-2-yl residue as substituent for the S1 pocket, displays excellent in vivo activity and superior drug-like properties.
