| Discovery of novel forkhead box O1 inhibitors for treating type 2 diabetes: improvement of fasting glycemia in diabetic db/db mice. | |
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MedLine Citation:
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PMID: 20736318 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Excessive hepatic glucose production through the gluconeogenesis pathway is partially responsible for the elevated glucose levels observed in patients with type 2 diabetes mellitus (T2DM). The forkhead transcription factor forkhead box O1 (Foxo1) plays a crucial role in mediating the effect of insulin on hepatic gluconeogenesis. Here, using a db/db mouse model, we demonstrate the effectiveness of Foxo1 inhibitor, an orally active small-molecule compound, as a therapeutic drug for treating T2DM. Using mass spectrometric affinity screening, we discovered a series of compounds that bind to Foxo1, identifying among them the compound, 5-amino-7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (AS1842856), which potently inhibits human Foxo1 transactivation and reduces glucose production through the inhibition of glucose-6 phosphatase and phosphoenolpyruvate carboxykinase mRNA levels in a rat hepatic cell line. Oral administration of AS1842856 to diabetic db/db mice led to a drastic decrease in fasting plasma glucose level via the inhibition of hepatic gluconeogenic genes, whereas administration to normal mice had no effect on the fasting plasma glucose level. Treatment with AS1842856 also suppressed an increase in plasma glucose level caused by pyruvate injection in both normal and db/db mice. Taken together, these findings indicate that the Foxo1 inhibitor represents a new class of drugs for use in treating T2DM. |
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Authors:
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Takeyuki Nagashima; Nobuharu Shigematsu; Riyo Maruki; Yasuharu Urano; Hirotsugu Tanaka; Akiyoshi Shimaya; Teruhiko Shimokawa; Masayuki Shibasaki |
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Publication Detail:
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Type: Journal Article Date: 2010-08-24 |
Journal Detail:
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Title: Molecular pharmacology Volume: 78 ISSN: 1521-0111 ISO Abbreviation: Mol. Pharmacol. Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-10-20 Completed Date: 2010-12-07 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0035623 Medline TA: Mol Pharmacol Country: United States |
Other Details:
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Languages: eng Pagination: 961-70 Citation Subset: IM |
Affiliation:
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Pharmacology Research Labs, Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan. takeyuki.nagashima@jp.astellas.com |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Line, Tumor Fasting Forkhead Transcription Factors / antagonists & inhibitors*, genetics Glucose / biosynthesis Glucose-6-Phosphatase / antagonists & inhibitors, genetics Humans Hyperglycemia / drug therapy*, metabolism Hypoglycemic Agents / pharmacology*, therapeutic use Male Mass Spectrometry Mice Nerve Tissue Proteins / antagonists & inhibitors Phosphoenolpyruvate Carboxykinase (GTP) / antagonists & inhibitors, genetics Pyruvic Acid / pharmacology Quinolones / pharmacology*, therapeutic use RNA, Messenger / antagonists & inhibitors Rats Structure-Activity Relationship Transcriptional Activation |
| Chemical | |
Reg. No./Substance:
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0/5-amino-7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 0/FOXO1 protein, human; 0/Forkhead Transcription Factors; 0/Foxo1 protein, mouse; 0/Hypoglycemic Agents; 0/Nerve Tissue Proteins; 0/Quinolones; 0/RNA, Messenger; 127-17-3/Pyruvic Acid; 147604-79-3/Foxo1 protein, rat; 50-99-7/Glucose; EC 3.1.3.9/Glucose-6-Phosphatase; EC 4.1.1.32/Phosphoenolpyruvate Carboxykinase (GTP) |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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