AZD 7545 is an inhibitor of pyruvate dehydrogenase (PDH) kinases (PDKs), resulting in an increase in PDH activity with an EC50 value of 5.2 nM for PDK2. It less potently inhibits PDK1 and PDK3 (IC50s = 87 and 600 nM, respectively). AZD 7545 stimulates pyruvate oxidation in rat hepatocytes (EC50 = 105 nM) and significantly elevates muscle PDH activity in obese Zucker rats. It elevates postprandial glucose levels and improves the 24 hour glucose profile in obese, insulin-resistant rats, compared with lean counterparts.
AZD7545 is a potent, competitive, selective PDHK2 (pyruvate dehydrogenase kinase 2) inhibitor with IC50s of 36.8 nM, 6.4 nM for PDHK1 and PDHK2, respectively[1].
ChEBI: AZD7545 is a sulfone that is benzene substituted by [4-(dimethylcarbamoyl)phenyl]sulfonyl, chloro and [(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]amino groups at positions 1, 3 and 4, respectively. It is a potent and non-ATP-competitive inhibitor of pyruvate dehydrogenase kinase 2 (PDHK2) with IC50 of 6.4 nM and exhibits glucose-lowering activity. Also inhibits PDHK1 at higher levels (IC50 = 36.8 nM). It has a role as a hypoglycemic agent and an EC 2.7.11.2 - [pyruvate dehydrogenase (acetyl-transferring)] kinase inhibitor. It is a member of benzamides, a sulfone, a tertiary alcohol, a tertiary carboxamide, a secondary carboxamide, a member of monochlorobenzenes and an organofluorine compound.
A single dose of AZD7545 (Oral administration; 10 mg/kg once a day (08:00 h) or Twice a day (08:00 and 18:00 h); for 7 days) to Wistar rats increases the proportion of liver PDH in its active, dephosphorylated form in a dose-related manner. A single dose of 10 mg/kg also significantly elevates muscle PDH activity in obese Zucker (fa/fa) rats[3].
| Animal Model: | Obese male (fa/fa) Zucker rats [3] |
| Dosage: | 10 mg/kg |
| Administration: | Oral administration; once a day (08:00 h) or Twice a day ( 08:00 and 18:00 h); for 7 days |
| Result: | Improved the control of blood glucose levels. |
[1] morrell j a, orme j, butlin r j, et al. azd7545 is a selective inhibitor of pyruvate dehydrogenase kinase 2. biochemical society transactions, 2003, 31(6): 1168-1170.
[2] mayers r m, butlin r j, kilgour e, et al. azd7545, a novel inhibitor of pyruvate dehydrogenase kinase 2 (pdhk2), activates pyruvate dehydrogenase in vivo and improves blood glucose control in obese (fa/fa) zucker rats. biochemical society transactions, 2003, 31(6): 1165-1167.
