Glutamic acid analogues as potent dipeptidyl peptidase IV and 8 inhibitors |
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Authors: | Lu I-Lin Lee Shiow-Ju Tsu Hsu Wu Su-Ying Kao Kuo-His Chien Chia-Hui Chang Ying-Ying Chen Yuan-Shou Cheng Jai-Hong Chang Chung-Nien Chen Tung-Wei Chang Sheng-Ping Chen Xin Jiaang Weir-Torn |
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Institution: | Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Rd., Zhunan Town, Miaoli Country 350, Taiwan, ROC. |
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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. |
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