4a5s
From Proteopedia
CRYSTAL STRUCTURE OF HUMAN DPP4 IN COMPLEX WITH A NOVAL HETEROCYCLIC DPP4 INHIBITOR
Structural highlights
Function[DPP4_HUMAN] Cell surface glycoprotein receptor involved in the costimulatory signal essential for T-cell receptor (TCR)-mediated T-cell activation. Acts as a positive regulator of T-cell coactivation, by binding at least ADA, CAV1, IGF2R, and PTPRC. Its binding to CAV1 and CARD11 induces T-cell proliferation and NF-kappa-B activation in a T-cell receptor/CD3-dependent manner. Its interaction with ADA also regulates lymphocyte-epithelial cell adhesion. In association with FAP is involved in the pericellular proteolysis of the extracellular matrix (ECM), the migration and invasion of endothelial cells into the ECM. May be involved in the promotion of lymphatic endothelial cells adhesion, migration and tube formation. When overexpressed, enhanced cell proliferation, a process inhibited by GPC3. Acts also as a serine exopeptidase with a dipeptidyl peptidase activity that regulates various physiological processes by cleaving peptides in the circulation, including many chemokines, mitogenic growth factors, neuropeptides and peptide hormones. Removes N-terminal dipeptides sequentially from polypeptides having unsubstituted N-termini provided that the penultimate residue is proline.[1] [2] [3] [4] [5] [6] [7] [8] [9] Publication Abstract from PubMedNovel deazaxanthine-based DPP-4 inhibitors have been identified that are potent (IC(50) <10nM) and highly selective versus other dipeptidyl peptidases. Their synthesis and SAR are reported, along with initial efforts to improve the PK profile through decoration of the deazaxanthine core. Optimisation of compound 3a resulted in the identification of compound (S)-4i, which displayed an improved in vitro and ADME profile. Further enhancements to the PK profile were possible by changing from the deazahypoxanthine to the deazaxanthine template, culminating in compound 12g, which displayed good ex vivo DPP-4 inhibition and a superior PK profile in rat, suggestive of once daily dosing in man. Novel heterocyclic DPP-4 inhibitors for the treatment of type 2 diabetes.,Sutton JM, Clark DE, Dunsdon SJ, Fenton G, Fillmore A, Harris NV, Higgs C, Hurley CA, Krintel SL, Mackenzie RE, Duttaroy A, Gangl E, Maniara W, Sedrani R, Namoto K, Ostermann N, Gerhartz B, Sirockin F, Trappe J, Hassiepen U, Baeschlin DK Bioorg Med Chem Lett. 2012 Feb 1;22(3):1464-8. Epub 2011 Nov 20. PMID:22177783[10] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Dipeptidyl-peptidase IV | Human | Baeschlin, D K | Clark, D E | Dunsdon, S J | Duttaroy, A | Fenton, G | Fillmore, A | Gangl, E | Gerhartz, B | Harris, N V | Hassiepen, U | Higgs, C | Hurley, C A | Krintel, S L | Kroemer, M | Mackenzie, R E | Maniara, W | Namoto, K | Ostermann, N | Sedrani, R | Sirockin, F | Sutton, J M | Trappe, J | Zink, F | Hydrolase | Novartis compound nvp-biv988 | Type 2 diabetes
