401564-34-9Relevant articles and documents
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
Yoshida, Tomohiro,Akahoshi, Fumihiko,Sakashita, Hiroshi,Kitajima, Hiroshi,Nakamura, Mitsuharu,Sonda, Shuji,Takeuchi, Masahiro,Tanaka, Yoshihito,Ueda, Naoko,Sekiguchi, Sumie,Ishige, Takayuki,Shima, Kyoko,Nabeno, Mika,Abe, Yuji,Anabuki, Jun,Soejima, Aki,Yoshida, Kumiko,Takashina, Yoko,Ishii, Shinichi,Kiuchi, Satoko,Fukuda, Sayaka,Tsutsumiuchi, Reiko,Kosaka, Keigo,Murozono, Takahiro,Nakamaru, Yoshinobu,Utsumi, Hiroyuki,Masutomi, Naoya,Kishida, Hiroyuki,Miyaguchi, Ikuko,Hayashi, Yoshiharu
, p. 5705 - 5719 (2012/10/30)
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 (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.
Lead optimization of [(S)-γ-(arylamino)prolyl]thiazolidine focused on γ-substituent: Indoline compounds as potent DPP-IV inhibitors
Sakashita, Hiroshi,Akahoshi, Fumihiko,Yoshida, Tomohiro,Kitajima, Hiroshi,Hayashi, Yoshiharu,Ishii, Shinichi,Takashina, Yoko,Tsutsumiuchi, Reiko,Ono, Satoshi
, p. 641 - 655 (2007/10/03)
Dipeptidyl peptidase IV (DPP-IV) inhibitors are looked to as a potential new antidiabetic agent class. A series of [(S)-γ-(arylamino)prolyl]thiazolidine compounds in which the electrophilic nitrile is removed are chemically stable DPP-IV inhibitors. To discover a structure for the γ-substituent of the proline moiety more suitable for interacting with the S2 pocket of DPP-IV, optimization focused on the γ-substituent was carried out. The indoline compound 22e showed a DPP-IV-inhibitory activity 100-fold more potent than that of the prolylthiazolidine 10 and comparable to that of NVP-DPP728. It also displayed improved inhibitory selectivity for DPP-IV over DPP8 and DPP9 compared to compound 10. Indoline compounds such as 22e have a rigid conformation with double restriction of the aromatic moiety by proline and indoline structures to promote interaction with the binding site in the S2 pocket of DPP-IV. The double restriction effect provides a potent inhibitory activity which compensates for the decrease in activity caused by removing the electrophilic nitrile.
PROLINE DERIVATIVES AND USE THEREOF AS DRUGS
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, (2008/06/13)
The present invention aims at providing compounds having therapeutic effects due to a DPP-IV inhibitory action, and satisfactory as pharmaceutical products. The present inventors have found that derivatives having a substituent introduced into the γ-position of proline represented by the formula (I) wherein each symbol is as defined in the specification, have a potent DPP-IV inhibitory activity, and completed the present invention by increasing the stability.
