Discovery of novel forkhead box O1 inhibitors for treating type 2 diabetes: improvement of fasting glycemia in diabetic db/db mice.
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.
Nagashima
Takeyuki
T
Pharmacology Research Labs, Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan. takeyuki.nagashima@jp.astellas.com
Shigematsu
Nobuharu
N
Maruki
Riyo
R
Urano
Yasuharu
Y
Tanaka
Hirotsugu
H
Shimaya
Akiyoshi
A
Shimokawa
Teruhiko
T
Shibasaki
Masayuki
M
D000818:Animals; D045744:Cell Line, Tumor; D005215:Fasting; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics; D005947:Glucose / Q000096:biosynthesis; D005952:Glucose-6-Phosphatase / Q000037:antagonists & inhibitors / Q000235:genetics; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy* / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000037:antagonists & inhibitors / Q000235:genetics; D019289:Pyruvic Acid / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D051381:Rats; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation
C553926:5-amino-7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007004:Hypoglycemic Agents; D009419:Nerve Tissue Proteins; D015363:Quinolones; D012333:RNA, Messenger; C074639:Foxo1 protein, rat; D019289:Pyruvic Acid; D005952:Glucose-6-Phosphatase; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D005947:Glucose