Design, Synthesis and Pharmacological Evaluation of Potent and Selective Dipeptidyl-Derived Inhibitors as New Class of Antidiabetic Drugs

Dipeptidyl Peptidase-IV (DPP IV) is a serine protease enzyme. It selectively cleaves first two amino acids (His- Ala/Gly) of 29 amino acids GLP-1 peptide and thereby makes it inactive. Thus, inhibition of DPP IV enzyme activity, using suitable DPP-IV inhibitor likely to increase the levels of endogenous intact and bioactive GLP-1 peptides, thereby, it acts as antidiabetic agents.

In this project, based upon SAR study of NVP-DPP728, we have designed new series of dipeptide based DPP-IV inhibitors, which mainly consist of five membere proline ring system, attached to sterically hindered aromatic acid, with suitable linker. Total 24 new compounds were prepared, using solid phase peptide synthesis (SPPS) approach and purified by prep-HPLC. All the test compounds were subjected for DPP IV inhibitory activity and also selectivity of test compounds was assessed against DPP8, DPP9 and QPP enzymes (in vitro). Most potent compounds from each series were subjected for in vivo antidiabetic activity. In vitro, compound IIIb and IIId was found to be most active (IC50 similar to sitagliptin) and selective. In vivo, compound IIIb showed significant blood glucose reduction @ 20 mg/kg dose (ip and oral route administration).