3VJL

Crystal structure of human depiptidyl peptidase IV (DPP-4) in complex with a prolylthiazolidine inhibitor #2

Summary for 3VJL

• Entry DOI: 10.2210/pdb3vjl/pdb
• Related: 3VJK 3VJM
• Descriptor: Dipeptidyl peptidase 4, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, [(2S,4S)-4-{4-[1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]piperidin-1-yl}pyrrolidin-2-yl](1,3-thiazolidin-3-yl)methanone, ... (5 entities in total)
• Functional Keywords: alpha/beta, beta-propeller, aminopeptidase, serine protease, signal-anchor, transmembrane, diabetes, glycoprotein, cell membrane, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 176168.44

Authors

Akahoshi, F.,Kishida, H.,Miyaguchi, I.,Yoshida, T.,Ishii, S. (deposition date: 2011-10-24, release date: 2012-10-24, Last modification date: 2024-10-16)

Primary citation

Yoshida, T.,Akahoshi, F.,Sakashita, H.,Kitajima, H.,Nakamura, M.,Sonda, S.,Takeuchi, M.,Tanaka, Y.,Ueda, N.,Sekiguchi, S.,Ishige, T.,Shima, K.,Nabeno, M.,Abe, Y.,Anabuki, J.,Soejima, A.,Yoshida, K.,Takashina, Y.,Ishii, S.,Kiuchi, S.,Fukuda, S.,Tsutsumiuchi, R.,Kosaka, K.,Murozono, T.,Nakamaru, Y.,Utsumi, H.,Masutomi, N.,Kishida, H.,Miyaguchi, I.,Hayashi, Y.
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., 20:5705-5719, 2012

PubMed Abstract: 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 (8 g), which has a unique structure characterized by five consecutive rings. An X-ray co-crystal structure of 8 g 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 8 g, at 0.03 mg/kg or higher doses, significantly inhibited the increase of plasma glucose levels after an oral glucose load in Zucker fatty rats. Compound 8 g (teneligliptin) has been approved for the treatment of type 2 diabetes in Japan.

PubMed: 22959556
DOI: 10.1016/j.bmc.2012.08.012

Experimental method

X-RAY DIFFRACTION (2.393 Å)