AZD7545

Description

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.

Definition

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.

References

[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.