Synthesis and biological evaluation of homopiperazine derivatives with β-aminoacyl group as dipeptidyl peptidase IV inhibitors

Ahn, Jin Hee; Park, Woul Seong; Jun, Mi Ae; Shin, Mi Sik; Kang, Seung Kyu; Kim, Ki Young; Rhee, Sang Dal; Bae, Myung Ae; Kim, Kwang-Rok; Kim, Sung Gyu; Kim, Sun Young; Sohn, Sang Kwon; Kang, Nam Sook; Lee, Jie‐Oh; Lee, Duck‐Hyung; Cheon, Hyae Gyeong; Kim, Sung Soo

doi:10.1016/j.bmcl.2008.10.076

Cited by 21 publications

(7 citation statements)

References 28 publications

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“…Some functionally important residues lining the active site in DPP4 such as Tyr547 and Asn710 [41], which are provided by the propeller domain, are not conserved in DPP7. In spite of the totally different “selectivity” domains, DPP4 and DPP7 still retain functionally conserved residues participating in both the recognition of the N-terminus of the substrate ( i.e.…”

Section: Resultsmentioning

confidence: 99%

Structures of Human DPP7 Reveal the Molecular Basis of Specific Inhibition and the Architectural Diversity of Proline-Specific Peptidases

et al. 2012

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Proline-specific dipeptidyl peptidases (DPPs) are emerging targets for drug development. DPP4 inhibitors are approved in many countries, and other dipeptidyl peptidases are often referred to as DPP4 activity- and/or structure-homologues (DASH). Members of the DASH family have overlapping substrate specificities, and, even though they share low sequence identity, therapeutic or clinical cross-reactivity is a concern. Here, we report the structure of human DPP7 and its complex with a selective inhibitor Dab-Pip (L-2,4-diaminobutyryl-piperidinamide) and compare it with that of DPP4. Both enzymes share a common catalytic domain (α/β-hydrolase). The catalytic pocket is located in the interior of DPP7, deep inside the cleft between the two domains. Substrates might access the active site via a narrow tunnel. The DPP7 catalytic triad is completely conserved and comprises Ser162, Asp418 and His443 (corresponding to Ser630, Asp708 and His740 in DPP4), while other residues lining the catalytic pockets differ considerably. The “specificity domains” are structurally also completely different exhibiting a β-propeller fold in DPP4 compared to a rare, completely helical fold in DPP7. Comparing the structures of DPP7 and DPP4 allows the design of specific inhibitors and thus the development of less cross-reactive drugs. Furthermore, the reported DPP7 structures shed some light onto the evolutionary relationship of prolyl-specific peptidases through the analysis of the architectural organization of their domains.

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Section: Resultsmentioning

confidence: 99%

Structures of Human DPP7 Reveal the Molecular Basis of Specific Inhibition and the Architectural Diversity of Proline-Specific Peptidases

et al. 2012

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“…Ninković et al also recently reported that a large number of phenyl-phenyl contacts in proteins had tilt angles above 60 , corresponding to the T-shaped interaction in the aromatic-aromatic interaction study at a tilt angle range from 0 (parallel) to 90 (T-shaped) by using PDB data 32 . With regard to the hydrogen bonding with the Tyr585, Ahn et al showed that a carboxyl substituent on the homopiperazine derivative appeared to interact with the OZ of Tyr585 in the co-crystal structure of DPP-4, and the acid moiety could regulate CYPs activities 33 .…”

Section: Sar Of Anagliptin Derivativesmentioning

confidence: 99%

Anagliptin, a potent dipeptidyl peptidase IV inhibitor: its single-crystal structure and enzyme interactions

Watanabe

Yasuda

Kojima

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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The single-crystal structure of anagliptin,-a]pyrimidine-6-carboxamide, was determined. Two independent molecules were held together by intermolecular hydrogen bonds, and the absolute configuration of the 2-cyanopyrrolidine ring delivered from L-prolinamide was confirmed to be S. The interactions of anagliptin with DPP-4 were clarified by the co-crystal structure solved at 2.85 Å resolution. Based on the structure determined by X-ray crystallography, the potency and selectivity of anagliptin were discussed, and an SAR study using anagliptin derivatives was performed.

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“…DPP4 and DPP6 have been shown to form dimers in solution 19 27 . The basis of homodimerization has been attributed to a 2190 Å 2 patch on DPP4 that encompasses the β-propeller and C-terminal loops (PDB-code: 3EIO) 35 . Analogous interactions are seen in DPP6 (PDB-code: 1XFD) and now also in our DPP10 structure, which buries 1580 Å 2 .…”

Section: Resultsmentioning

confidence: 99%

Structure of human dipeptidyl peptidase 10 (DPPY): a modulator of neuronal Kv4 channels

Bezerra

Dobrovetsky

Seitova

et al. 2015

Sci Rep

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The voltage-gated potassium channel family (Kv) constitutes the most diverse class of ion channels in the nervous system. Dipeptidyl peptidase 10 (DPP10) is an inactive peptidase that modulates the electrophysiological properties, cell-surface expression and subcellular localization of voltage-gated potassium channels. As a consequence, DPP10 malfunctioning is associated with neurodegenerative conditions like Alzheimer and fronto-temporal dementia, making this protein an attractive drug target. In this work, we report the crystal structure of DPP10 and compare it to that of DPP6 and DPP4. DPP10 belongs to the S9B serine protease subfamily and contains two domains with two distinct folds: a β-propeller and a classical α/β-hydrolase fold. The catalytic serine, however, is replaced by a glycine, rendering the protein enzymatically inactive. Difference in the entrance channels to the active sites between DPP10 and DPP4 provide an additional rationale for the lack of activity. We also characterize the DPP10 dimer interface focusing on the alternative approach for designing drugs able to target protein-protein interactions.

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Synthesis and biological evaluation of homopiperazine derivatives with β-aminoacyl group as dipeptidyl peptidase IV inhibitors

Cited by 21 publications

References 28 publications

Structures of Human DPP7 Reveal the Molecular Basis of Specific Inhibition and the Architectural Diversity of Proline-Specific Peptidases

Structures of Human DPP7 Reveal the Molecular Basis of Specific Inhibition and the Architectural Diversity of Proline-Specific Peptidases

Anagliptin, a potent dipeptidyl peptidase IV inhibitor: its single-crystal structure and enzyme interactions

Structure of human dipeptidyl peptidase 10 (DPPY): a modulator of neuronal Kv4 channels

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