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. 2012 Oct 1;20(19):5705-19. doi: 10.1016/j.bmc.2012.08.012.
Tomohiro Yoshida  1 ,  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 ,  Sayaka Fukuda ,  Reiko Tsutsumiuchi ,  Keigo Kosaka ,  Takahiro Murozono ,  Yoshinobu Nakamaru ,  Hiroyuki Utsumi ,  Naoya Masutomi ,  Hiroyuki Kishida ,  Ikuko Miyaguchi ,  Yoshiharu Hayashi
Affiliations
  • 1. Research Division, Mitsubishi Tanabe Pharma Corporation, 2-2-50, Kawagishi, Toda-shi, Saitama 335-8505, Japan.
PMID: 22959556 DOI: 10.1016/j.bmc.2012.08.012
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.

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