Hit Selection of Dipeptidyl Peptidase-4 Inhibitors Bearing Thieno[2,3-d]Pyrimidine Scaffold

The thieno[2,3-d]pyrimidine fragment is in the structure of many drug-like candidate derivatives with a wide range of biological activities. However, very few dipeptidyl peptidase-4 (DPP-4) inhibitors with this building block are currently known. Here, the selection of a novel DPP-4 Inhibitor based on the thienopyrimidine scaffold is reported. In the performed study, ethyl 4-amino-5-methyl-2-(3-(trifluoromethyl)phenyl)thieno[2,3-d]pyrimidine-6-carboxylate (compound 22) demonstrated DPP-4 inhibitory potential about twice higher than that of the reference inhibitor diprotin A. The manner of inhibition is noncompetitive, a rare type among DPP-4 inhibitors. The molecular docking highlighted the importance of Ser349, Asn377, Glu378, Phe396, and Asp588 in forming the inhibitor/DPP-4 complex. Compound 22 might be useful as a source of ideas contributing to the design and further changes and optimizations of thieno[2,3-d]pyrimidine-based DPP-4 inhibitors.

dipeptidyl peptidase‐4; inhibitors; molecular dynamics; noncompetitive DPP‐4 inhibition; thieno[2,3‐d]pyrimidine.