| Title : Discovery and preclinical profile of teneligliptin (3-[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-y lcarbonyl]thiazolidine): a highly potent, selective, long-lasting and orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes - Yoshida_2012_Bioorg.Med.Chem_20_5705 |
| Author(s) : Yoshida T , Akahoshi F , Sakashita H , Kitajima H , Nakamura M , Sonda S , Takeuchi M , Tanaka Y , Ueda N , Sekiguchi S , Ishige T , Shima K , Nabeno M , Abe Y , Anabuki J , Soejima A , Yoshida K , Takashina Y , Ishii S , Kiuchi S , Fukuda S , Tsutsumiuchi R , Kosaka K , Murozono T , Nakamaru Y , Utsumi H , Masutomi N , Kishida H , Miyaguchi I , Hayashi Y |
| Ref : Bioorganic & Medicinal Chemistry , 20 :5705 , 2012 |
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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 gamma-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-yl carbonyl]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. |
| PubMedSearch : Yoshida_2012_Bioorg.Med.Chem_20_5705 |
| PubMedID: 22959556 |
| Gene_locus related to this paper: human-DPP4 |
| Inhibitor | CHEMBL2147710 Teneligliptin |
| Gene_locus | human-DPP4 |
| Structure | 3VJK 3VJL |
Yoshida T, Akahoshi F, Sakashita H, Kitajima H, Nakamura M, Sonda S, Takeuchi M, Tanaka Y, Ueda N, Sekiguchi S, Ishige T, Shima K, Nabeno M, Abe Y, Anabuki J, Soejima A, Yoshida K, Takashina Y, Ishii S, Kiuchi S, Fukuda S, Tsutsumiuchi R, Kosaka K, Murozono T, Nakamaru Y, Utsumi H, Masutomi N, Kishida H, Miyaguchi I, Hayashi Y (2012)
Discovery and preclinical profile of teneligliptin (3-[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-y lcarbonyl]thiazolidine): a highly potent, selective, long-lasting and orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes
Bioorganic & Medicinal Chemistry
20 :5705
Yoshida T, Akahoshi F, Sakashita H, Kitajima H, Nakamura M, Sonda S, Takeuchi M, Tanaka Y, Ueda N, Sekiguchi S, Ishige T, Shima K, Nabeno M, Abe Y, Anabuki J, Soejima A, Yoshida K, Takashina Y, Ishii S, Kiuchi S, Fukuda S, Tsutsumiuchi R, Kosaka K, Murozono T, Nakamaru Y, Utsumi H, Masutomi N, Kishida H, Miyaguchi I, Hayashi Y (2012)
Bioorganic & Medicinal Chemistry
20 :5705