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PDBsum entry 3vjk
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Hydrolase/hydrolase inhibitor
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PDB id
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3vjk
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PDB id:
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| Name: |
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Hydrolase/hydrolase inhibitor
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Title:
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Crystal structure of human depiptidyl peptidase iv (dpp-4) in complex with mp-513
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Structure:
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Dipeptidyl peptidase 4. Chain: a, b. Fragment: unp residues 33-766. Synonym: adabp, adenosine deaminase complexing protein 2, adcp-2, dipeptidyl peptidase iv, dpp iv, t-cell activation antigen cd26, tp103, dipeptidyl peptidase 4 membrane form, dipeptidyl peptidase iv membrane form, dipeptidyl peptidase 4 soluble form, dipeptidyl peptidase iv soluble form. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: dpp4, adcp2, cd26. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: expressf+.
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Resolution:
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2.49Å
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R-factor:
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0.228
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R-free:
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0.279
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Authors:
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F.Akahoshi,H.Kishida,I.Miyaguchi,T.Yoshida,S.Ishii
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Key ref:
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T.Yoshida
et al.
(2012).
Discovery and preclinical profile of teneligliptin (3-[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl]thiazolidine): a highly potent, selective, long-lasting and orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.
Bioorg Med Chem Lett,
20,
5705-5719.
PubMed id:
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Date:
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24-Oct-11
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Release date:
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24-Oct-12
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PROCHECK
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Headers
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References
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P27487
(DPP4_HUMAN) -
Dipeptidyl peptidase 4 from Homo sapiens
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Seq:
Struc:
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766 a.a.
729 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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Enzyme class:
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E.C.3.4.14.5
- dipeptidyl-peptidase Iv.
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Reaction:
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Release of an N-terminal dipeptide, Xaa-Xbb-|-Xcc, from a polypeptide, preferentially when Xbb is Pro, provided Xcc is neither Pro nor hydroxyproline.
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Bioorg Med Chem Lett
20:5705-5719
(2012)
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PubMed id:
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Discovery and preclinical profile of teneligliptin (3-[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl]thiazolidine): a highly potent, selective, long-lasting and orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.
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T.Yoshida,
F.Akahoshi,
H.Sakashita,
H.Kitajima,
M.Nakamura,
S.Sonda,
M.Takeuchi,
Y.Tanaka,
N.Ueda,
S.Sekiguchi,
T.Ishige,
K.Shima,
M.Nabeno,
Y.Abe,
J.Anabuki,
A.Soejima,
K.Yoshida,
Y.Takashina,
S.Ishii,
S.Kiuchi,
S.Fukuda,
R.Tsutsumiuchi,
K.Kosaka,
T.Murozono,
Y.Nakamaru,
H.Utsumi,
N.Masutomi,
H.Kishida,
I.Miyaguchi,
Y.Hayashi.
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ABSTRACT
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Dipeptidyl peptidase IV (DPP-4) inhibition is suitable mechanism for once daily
oral dosing regimen because of its low risk of hypoglycemia. We explored linked
bicyclic heteroarylpiperazines substituted at the γ-position of the proline
structure in the course of the investigation of l-prolylthiazolidines. The
efforts led to the discovery of a highly potent, selective, long-lasting and
orally active DPP-4 inhibitor,
3-[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl]thiazolidine
(8g), which has a unique structure characterized by five consecutive rings. An
X-ray co-crystal structure of 8g in DPP-4 demonstrated that the key interaction
between the phenyl ring on the pyrazole and the S(2) extensive subsite of DPP-4
not only boosted potency, but also increased selectivity. Compound 8g, at
0.03mg/kg or higher doses, significantly inhibited the increase of plasma
glucose levels after an oral glucose load in Zucker fatty rats. Compound 8g
(teneligliptin) has been approved for the treatment of type 2 diabetes in Japan.
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