Document Detail

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.
MedLine Citation:
PMID:  22959556     Owner:  NLM     Status:  MEDLINE    
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.
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
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Publication Detail:
Type:  Journal Article     Date:  2012-08-17
Journal Detail:
Title:  Bioorganic & medicinal chemistry     Volume:  20     ISSN:  1464-3391     ISO Abbreviation:  Bioorg. Med. Chem.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-09-21     Completed Date:  2013-02-08     Revised Date:  2013-03-26    
Medline Journal Info:
Nlm Unique ID:  9413298     Medline TA:  Bioorg Med Chem     Country:  England    
Other Details:
Languages:  eng     Pagination:  5705-19     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier Ltd. All rights reserved.
Research Division, Mitsubishi Tanabe Pharma Corporation, 2-2-50, Kawagishi, Toda-shi, Saitama 335-8505, Japan.
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MeSH Terms
Blood Glucose / metabolism
Crystallography, X-Ray
Diabetes Mellitus, Type 2 / drug therapy*,  enzymology
Dipeptidyl Peptidase 4 / metabolism
Dipeptidyl-Peptidase IV Inhibitors / chemistry*,  pharmacokinetics,  pharmacology,  therapeutic use*
Glucose Tolerance Test
Hypoglycemic Agents / chemistry*,  pharmacokinetics,  pharmacology,  therapeutic use*
Molecular Docking Simulation
Pyrazoles / chemistry*,  pharmacokinetics,  pharmacology,  therapeutic use*
Rats, Wistar
Rats, Zucker
Thiazolidines / chemistry*,  pharmacokinetics,  pharmacology,  therapeutic use*
Reg. No./Substance:
0/3-(4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-ylcarbonyl)thiazolidine; 0/Blood Glucose; 0/Dipeptidyl-Peptidase IV Inhibitors; 0/Hypoglycemic Agents; 0/Pyrazoles; 0/Thiazolidines; EC Peptidase 4

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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