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-ylcarbonyl]thiazolidine): a highly potent, selective, long-lasting and orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.
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.
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, 2-2-50, Kawagishi, Toda-shi, Saitama 335-8505, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Yoshida
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Akahoshi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakashita
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kitajima
authors.forename: Mitsuharu
authors.initials: M
authors.lastname: Nakamura
authors.forename: Shuji
authors.initials: S
authors.lastname: Sonda
authors.forename: Masahiro
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Naoko
authors.initials: N
authors.lastname: Ueda
authors.forename: Sumie
authors.initials: S
authors.lastname: Sekiguchi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ishige
authors.forename: Kyoko
authors.initials: K
authors.lastname: Shima
authors.forename: Mika
authors.initials: M
authors.lastname: Nabeno
authors.forename: Yuji
authors.initials: Y
authors.lastname: Abe
authors.forename: Jun
authors.initials: J
authors.lastname: Anabuki
authors.forename: Aki
authors.initials: A
authors.lastname: Soejima
authors.forename: Kumiko
authors.initials: K
authors.lastname: Yoshida
authors.forename: Yoko
authors.initials: Y
authors.lastname: Takashina
authors.forename: Shinichi
authors.initials: S
authors.lastname: Ishii
authors.forename: Satoko
authors.initials: S
authors.lastname: Kiuchi
authors.forename: Sayaka
authors.initials: S
authors.lastname: Fukuda
authors.forename: Reiko
authors.initials: R
authors.lastname: Tsutsumiuchi
authors.forename: Keigo
authors.initials: K
authors.lastname: Kosaka
authors.forename: Takahiro
authors.initials: T
authors.lastname: Murozono
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Nakamaru
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Utsumi
authors.forename: Naoya
authors.initials: N
authors.lastname: Masutomi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kishida
authors.forename: Ikuko
authors.initials: I
authors.lastname: Miyaguchi
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Hayashi
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D018360:Crystallography, X-Ray; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000201:enzymology; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D005951:Glucose Tolerance Test; D000882:Haplorhini; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D062105:Molecular Docking Simulation; D011720:Pyrazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D011924:Rats, Zucker; D053778:Thiazolidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C579035:3-(4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-ylcarbonyl)thiazolidine; D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D011720:Pyrazoles; D053778:Thiazolidines; D018819:Dipeptidyl Peptidase 4