Glutamic acid analogues as potent dipeptidyl peptidase IV and 8 inhibitors.

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Lu IL, Lee SJ, Tsu H, Wu SY, Kao KH, Chien CH, Chang YY, Chen YS, Cheng JH, Chang CN, Chen TW, Chang SP, Chen X, Jiaang WT

Glutamic acid analogues as potent dipeptidyl peptidase IV and 8 inhibitors.

Bioorg Med Chem Lett. 2005 Jul 1;15(13):3271-5.

PubMed ID

15927466 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Vildagliptin	Dipeptidyl peptidase 4	IC 50 (nM)	51	N/A	N/A	Details