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Merck
  • 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.

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.

Bioorganic & medicinal chemistry (2012-09-11)
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, Sayaka Fukuda, Reiko Tsutsumiuchi, Keigo Kosaka, Takahiro Murozono, Yoshinobu Nakamaru, Hiroyuki Utsumi, Naoya Masutomi, Hiroyuki Kishida, Ikuko Miyaguchi, Yoshiharu Hayashi
RESUMEN

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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Diclofenac, ≥98% (HPLC)