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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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References listed in PDB file
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Key reference
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Title
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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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Authors
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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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Ref.
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Bioorg Med Chem Lett, 2012,
20,
5705-5719.
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PubMed id
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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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