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
| Autor: | Takayuki Ishige, Hiroyuki Kishida, Sumie Sekiguchi, Yoshihito Tanaka, Yuji Abe, Yoshinobu Nakamaru, Ikuko Miyaguchi, Hiroshi Kitajima, Keigo Kosaka, Kumiko Yoshida, Reiko Tsutsumiuchi, Naoko Ueda, Mika Nabeno, Masahiro Takeuchi, Shinichi Ishii, Yoko Takashina, Hiroyuki Utsumi, Tomohiro Yoshida, Satoko Kiuchi, Yoshiharu Hayashi, Kyoko Shima, Shuji Sonda, Aki Soejima, Naoya Masutomi, Jun Anabuki, Fukuda Sayaka, Hiroshi Sakashita, Mitsuharu Nakamura, Takahiro Murozono, Fumihiko Akahoshi |
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| Rok vydání: | 2012 |
| Předmět: |
Blood Glucose
Male Stereochemistry Dipeptidyl Peptidase 4 Clinical Biochemistry Thiazolidine Pharmaceutical Science Pyrazole Crystallography X-Ray Biochemistry Dipeptidyl peptidase chemistry.chemical_compound Oral administration Drug Discovery medicine Animals Humans Hypoglycemic Agents Teneligliptin Rats Wistar Molecular Biology Glucose tolerance test Dipeptidyl-Peptidase IV Inhibitors medicine.diagnostic_test biology Bicyclic molecule Organic Chemistry Haplorhini Glucose Tolerance Test Rats Rats Zucker Molecular Docking Simulation chemistry Diabetes Mellitus Type 2 Enzyme inhibitor biology.protein Molecular Medicine Pyrazoles Thiazolidines medicine.drug |
| Zdroj: | Bioorganicmedicinal chemistry. 20(19) |
| ISSN: | 1464-3391 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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