Author/Authors :
I-Lin Lu، نويسنده , , Shiow-Ju Lee، نويسنده , , Hsu Tsu، نويسنده , , Su-Ying Wu، نويسنده , , Kuo-Yuan Kao، نويسنده , , Chia-Hui Chien، نويسنده , , Ying-Ying Chang، نويسنده , , Yuan-Shou Chen، نويسنده , , Jai-Hong Cheng، نويسنده , , Chung-Nien Chang، نويسنده , , Tung-Wei Chen، نويسنده , , Sheng-Ping Chang، نويسنده , , Xin Chen، نويسنده , , Weir-Torn Jiaang، نويسنده ,
Abstract :
To find potent and selective inhibitors of dipeptidyl peptidase IV (DPP-IV), we synthesized a series of 2-cyanopyrrolidine with P2-site 4-substituted glutamic acid derivatives and tested their activities against DPP-IV, DPP8, and DPP-II. Analogues that incorporated a bulky substituent at the first carbon position of benzylamine or isoquinoline showed over 30-fold selectivity for DPP-IV over both DPP8 and DPP-II. From structure–activity relationship studies, we speculate that the S2 site of DPP8 might be similar to that of DPP-IV, while DPP-IV inhibitor with N-substituted glycine in the P2 site and/or with a moiety involving in hydrophobic interaction with the side chain of Phe357 might provide a better selectivity for DPP-IV over DPP8.
