PDHK (pyruvate dehydrogenase kinase) is a kinase enzyme which acts to inactivate the enzyme pyruvate dehydrogenase by phosphorylating it using ATP. AZD7545 is a novel PDHK inhibitor with IC50 values of 36.8nM/6.4nM for PDHK1/2[3], and EC50 value of 5.2nM for increasing PDH activity. It stimulated the rate of pyruvate oxidation with EC50 value of 105nM in rat hepatocytes. A single dose of AZD7545 to Wistar rats increased the proportion of liver PDH in its active, dephosphorylated form in a dose-related manner from 24.7 to 70.3% at 30 mg/kg; and in skeletal muscle from 21.1 to 53.3%. A single dose of 10 mg/kg also significantly elevated muscle PDH activity in obese Zucker (fa/fa) rats. AZD7545 (10 mg/kg) twice daily for 7 days markedly improved the 24-h glucose profile, by eliminating the postprandial elevation in blood glucose[4]. AZD7545 failed to inhibit PDHK4 and paradoxically, at higher concentrations (>10 nM), AZD7545 stimulated PDHK4 activity[3].
作用机制
AZD7545 docks into the lipoamide-binding site on PDHK2 thus inhibiting interaction with the E2 subunit. It inhibits PDHK in a non-ATP competitive manner.[3]
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