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

ABSTRACT 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.