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 t

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• 作者：Tomohiro Yoshida ; Fumihiko Akahoshi ; Hiroshi Sakashita ; Hiroshi Kitajima ; Mitsuharu Nakamura ; Shuji Sonda ; Masahiro Takeuchi ; Yoshihito Tanaka ; Naoko Ueda ; Sumie Sekiguchi ; Takayuki Ishige ; Kyoko Shima ; Mika Nabeno ; Yuji Abe ; Jun Anabuki ; Aki Soejima ; Kumiko Yoshida ; Yoko Takashina ; Shinichi Ishii ; Satoko Kiuchi ; et al.
• 关键词：DPP-4 inhibitor ; Thiazolidine ; Bicyclic heteroarylpiperazine
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 出版时间：1 October, 2012
• 年：2012
• 卷：20
• 期：19
• 页码：5705-5719
• 全文大小：1452 K

文摘

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 ¦Ã-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 S₂ extensive subsite of DPP-4 not only boosted potency, but also increased selectivity. Compound 8g, 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 8g (teneligliptin) has been approved for the treatment of type 2 diabetes in Japan.