title: 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.
abstract: PDH (pyruvate dehydrogenase) is a key enzyme controlling the rate of glucose oxidation, and the availability of gluconeogenic precursors. Activation of PDH in skeletal muscle and liver may increase glucose uptake and reduce glucose production. This study describes the properties of AZD7545, a novel, small-molecule inhibitor of PDHK (PDH kinase). In the presence of PDHK2, AZD7545 increased PDH activity with an EC(50) value of 5.2 nM. In rat hepatocytes, the rate of pyruvate oxidation was stimulated 2-fold (EC(50) 105 nM). 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. Obese, insulin-resistant, Zucker rats show elevated postprandial glucose levels compared with their lean counterparts (8.7 versus 6.1 mM at 12 weeks old). AZD7545 (10 mg/kg) twice daily for 7 days markedly improved the 24-h glucose profile, by eliminating the postprandial elevation in blood glucose. These results suggest that PDHK inhibitors may be beneficial agents for improving glucose control in the treatment of type 2 diabetes.
authors.affiliation: AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K. rachel.mayers@astrazeneca.com
authors.forename: R M
authors.initials: RM
authors.lastname: Mayers
authors.forename: R J
authors.initials: RJ
authors.lastname: Butlin
authors.forename: E
authors.initials: E
authors.lastname: Kilgour
authors.forename: B
authors.initials: B
authors.lastname: Leighton
authors.forename: D
authors.initials: D
authors.lastname: Martin
authors.forename: J
authors.initials: J
authors.lastname: Myatt
authors.forename: J P
authors.initials: JP
authors.lastname: Orme
authors.forename: B R
authors.initials: BR
authors.lastname: Holloway
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D009765:Obesity / Q000097:blood / Q000201:enzymology*; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D051381:Rats; D011924:Rats, Zucker
chemical_list: D001786:Blood Glucose; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases