Nananoic acid derivatives as dipeptidyl peptidase inhibitors

摘要

The present invention is directed to novel nananoic acid derivatives which are inhibitors of the dipeptidyl peptidase-IV enzyme ("DPP-IV inhibitors") and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, particularly in the treatment of type 2 diabetes and conditions that are associated with the same. In addition, the present invention provides pharmaceutical compositions useful in inhibiting DPP-IV enzyme, comprising a therapeutically effective amount of nananoic acid derivatives. Moreover, the present invention provides a method of inhibiting DPP-IV comprising administering to a mammal in need of such treatment a therapeutically effective amount of a single or a combination of nananoic acid derivatives of the invention. The invention further relates to the kits and other articles of manufacture for treating disease states associated with DPP-IV enzyme. The invention further relates to a method of identifying a compound that has dipeptidyl peptidase-IV enzyme inhibition activity, comprising following steps: 1. Define the residues of the active site of DPP-IV 2. Define the geometry and force field relationship of the residues identified above in (1) 3. Define the physical parameters of the active site identified in (1) 4. Validate the model based on mutational analysis and in-vitro inhibitor binding studies 5. Screen the library for scaffolds and small molecules that satisfy the model developed in (3) and validated in (4) above. 6. Dock each inhibitor identified in (5) above to the active site of DPP-IV defined in (1). 7. Minimize the energy of the inhibitor and DPP-IV complex using force fields used in (2) above. 8. Compare the energy of interaction of each inhibitor to that of known inhibitors. 9. Synthesize and validate in in-vitro assays