Glutamic acid analogues as potent dipeptidyl peptidase IV and 8 inhibitors
2005
Abstract—To find potent and selective inhibitors of dipeptidyl peptidase IV (DPP-IV), we synthesized a series of 2-cyanopyrrolidinewith P2-site 4-substituted glutamic acid derivatives and tested their activities against DPP-IV, DPP8, and DPP-II. Analogues thatincorporated 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 similarto that of DPP-IV, while DPP-IV inhibitor with N-substituted glycine in the P2 site and/or with a moiety involving in hydrophobicinteraction with the side chain of Phe357 might provide a better selectivity for DPP-IV over DPP8. 2005 Elsevier Ltd. All rights reserved. Dipeptidyl peptidase IV (DPP-IV, also known as CD26)(EC 3.4.14.5) is a drug target for type II diabetes. It is aprolyl dipeptidase involved in the in vivo degradation oftwo insulin-sensing hormones, glucagon-like peptide 1(GLP-1) and glucose-dependent insulinotropic polypep-tide (GIP), by cleaving at the peptide bond of the penul-timate position.
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