Anilides of (<i>R</i>)-Trifluoro-2-hydroxy-2-methylpropionic Acid as Inhibitors of Pyruvate Dehydrogenase Kinase

Bebernitz, Gregory R.; Aicher, Thomas D.; Stanton, James L.; Gao, Jiaping; Shetty, Suraj S.; Knorr, Douglas C.; Strohschein, Robert J.; Tan, Jennifer H.; Brand, Leonard; Liu, Charles; Wang, Wei H.; Vinluan, Christine C.; Kaplan, Emma L.; Dragland, Carol J.; DelGrande, Dominick; Islam, Amin; Lozito, Robert J.; Li, Xilin; Maniara, Wieslawa; Mann, W.

doi:10.1021/jm0000923

Cited by 59 publications

(29 citation statements)

References 44 publications

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“…More potent PDK inhibitors have been developed recently. SDZ048-619 increases PDC activity in tissues of the hyperglycemic Zucker diabetic fatty rat and reduces blood lactate but, surprisingly, not blood glucose (1,6). However, AZD7545, a specific PDK2 inhibitor, markedly lowers blood glucose in hyperglycemic Zucker diabetic fatty rats (30,31).…”

Section: Discussionmentioning

confidence: 99%

Pyruvate dehydrogenase kinase-4 deficiency lowers blood glucose and improves glucose tolerance in diet-induced obese mice

Jeoung¹,

Harris²

2008

American Journal of Physiology-Endocrinology and Metabolism

139

126

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Jeoung NH, Harris RA. Pyruvate dehydrogenase kinase-4 deficiency lowers blood glucose and improves glucose tolerance in diet-induced obese mice. Am J Physiol Endocrinol Metab 295: E46 -E54, 2008. First published April 22, 2008 doi:10.1152/ajpendo.00536.2007.-The effect of pyruvate dehydrogenase kinase-4 (PDK4) deficiency on glucose homeostasis was studied in mice fed a high-fat diet. Expression of PDK4 was greatly increased in skeletal muscle and diaphragm but not liver and kidney of wild-type mice fed the high-fat diet. Wild-type and PDK4 Ϫ/Ϫ mice consumed similar amounts of the diet and became equally obese. Insulin resistance developed in both groups. Nevertheless, fasting blood glucose levels were lower, glucose tolerance was slightly improved, and insulin sensitivity was slightly greater in the PDK4 Ϫ/Ϫ mice compared with wild-type mice. When the mice were killed in the fed state, the actual activity of the pyruvate dehydrogenase complex (PDC) was higher in the skeletal muscle and diaphragm but not in the liver and kidney of PDK4 Ϫ/Ϫ mice compared with wild-type mice. When the mice were killed after overnight fasting, the actual PDC activity was higher only in the kidney of PDK4 Ϫ/Ϫ mice compared with wild-type mice. The concentrations of gluconeogenic substrates were lower in the blood of PDK4 Ϫ/Ϫ mice compared with wild-type mice, consistent with reduced formation in peripheral tissues. Diaphragms isolated from PDK4 Ϫ/Ϫ mice oxidized glucose faster and fatty acids slower than diaphragms from wild-type mice. Fatty acid oxidation inhibited glucose oxidation by diaphragms from wild-type but not PDK4 Ϫ/Ϫ mice. NEFA, ketone bodies, and branched-chain amino acids were elevated more in PDK4 Ϫ/Ϫ mice, consistent with slower rates of oxidation. These findings show that PDK4 deficiency lowers blood glucose and slightly improves glucose tolerance and insulin sensitivity in mice with diet-induced obesity.pyruvate dehydrogenase kinase-4-knockout mice; diet-induced obesity; glucose oxidation; fatty acid oxidation; branched-chain amino acids THE PYRUVATE DEHYDROGENASE COMPLEX (PDC) is required for the oxidative disposal of dietary carbohydrate. Decarboxylation of pyruvate produces acetyl-CoA for oxidation by the citric acid cycle or conversion to fat. Since acetyl-CoA cannot be converted back to glucose, tight control of flux through PDC is required for maintenance of euglycemia during starvation. PDC activity has to be increased after meals but reduced during fasting. PDC activity is regulated by feedback inhibition by its products acetyl-CoA and NADH and by a balance between inactivation by pyruvate dehydrogenase kinases (PDKs) and activation by pyruvate dehydrogenase phosphatases (PDPs). In the well-fed state, PDC is relatively dephosphorylated and active for disposal of excess glucose. In the fasted state, PDC is highly phosphorylated and inactive so that three-carbon compounds can be converted back to glucose (50, 51). Four PDK isoenzymes (PDK1-4) and two PDP isoenzymes (PDP1 and -2) are expressed in mammalian tis...

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Section: Discussionmentioning

confidence: 99%

Pyruvate dehydrogenase kinase-4 deficiency lowers blood glucose and improves glucose tolerance in diet-induced obese mice

Jeoung¹,

Harris²

2008

American Journal of Physiology-Endocrinology and Metabolism

139

126

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“…A number of PDHK inhibitors have been tested in hyperglycaemic animal models. DCA, dosed to 12-week-old ZDF rats increased the PDH activity in tibialis anterior and cardiac muscle, kidney and liver, and decreased glucose levels, with sustained efficacy after 25 days of dosing [30] However, the same authors tested two novel PDHK inhibitors [30][31][32] in 24 h fasted, 8-week-old ZDF rats. Significant increases in PDH activity were demonstrated in the same four tissues, but these were, however, of smaller magnitude than reported for DCA (Table 2), and although plasma lactate levels were decreased, no glucose lowering was observed over an 11 day dosing period.…”

Section: Glucose Lowering In Animal Models Of Diabetesmentioning

confidence: 99%

PDH kinase inhibitors: a novel therapy for Type II diabetes?

Mayers

Leighton

Kilgour

2005

Biochemical Society Transactions

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The pyruvate dehydrogenase multienzyme complex catalyses the oxidative decarboxylation of pyruvate, which is an important regulatory step in oxidative metabolism. Phosphorylation of the E1 (pyruvate decarboxylase) subunit on one of three specific serine residues results in loss of enzyme activity. Four dedicated PDHK (pyruvate dehydrogenase kinase) isoenzymes have been identified, each of which display a distinct tissue-specific expression profile, and have differential regulatory properties. Thus PDHK play a key role in controlling the balance between glucose and lipid oxidation according to substrate supply. Increasing glucose oxidation by inhibiting PDHK may be an effective mechanism to increase glucose utilization; additionally, increasing pyruvate oxidation may further contribute to lowering of glucose level by decreasing the supply of gluconeogenic substrates. A number of PDHK inhibitors are now available to enable this mechanism to be evaluated as a therapy for diabetes. The isoenzyme selectivity profile of AZD7545 and related compounds will be described and evidence for their non-ATP-competitive mode of action presented. These compounds increase PDH activity in vivo, and when dosed chronically, improve glycaemic control in Zucker rats. Furthermore, glucose lowering has been demonstrated in the hyperglycaemic Zucker diabetic fatty rat. This result supports the hypothesis that inhibition of PDHK may be an effective therapy for Type II diabetes.

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“…Reductively acetylated GST-L2 supports the highest activity (increases from 80 to 130 nmol·min À1 ·mg À1 ) whereas reductive acetylation of GST-L1 gives by far the highest fold-increase (from 14 to 95 nmol·-min À1 ·mg À1 ) [110]. High-throughput screening followed by extensive synthetic refinements generated a potent class of PDK inhibitors that are amides of trifluoro-2-hydroxy-2-menthylpropionate [123][124][125][126][127]. Nov3r was the first high-potency inhibitor described in this class [123].…”

mentioning

confidence: 99%

“…Initial studies using DCA were encouraging [145], but this compound is a weak PDK inhibitor and a toxic metabolite [146][147][148]. With the objective of designing potent drugs to increase the metabolic use of glucose in individuals with type II diabetes, Glaxo [134], Novartis [123][124][125]149], AstraZeneca [126,135,136], and Pfizer [64] have produced PDK inhibitors. Novartis and AstraZeneca developed the class of tight-binding inhibitors that are amides of trifluoro-2-hydroxy-2-methylpropionic acid [123-126, 135, 136].…”

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confidence: 99%

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Pyruvate dehydrogenase kinase regulatory mechanisms and inhibition in treating diabetes, heart ischemia, and cancer

Roche

Hiromasa

2007

Cell. Mol. Life Sci.

235

249

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The fraction of pyruvate dehydrogenase complex (PDC) in the active form is reduced by the activities of dedicated PD kinase isozymes (PDK1, PDK2, PDK3 and PDK4). Via binding to the inner lipoyl domain (L2) of the dihydrolipoyl acetyltransferase (E2 60mer), PDK rapidly access their E2-bound PD substrate. The E2-enhanced activity of the widely distributed PDK2 is limited by dissociation of ADP from its C-terminal catalytic domain, and this is further slowed by pyruvate binding to the N-terminal regulatory (R) domain. Via the reverse of the PDC reaction, NADH and acetyl-CoA reductively acetylate lipoyl group of L2, which binds to the R domain and stimulates PDK2 activity by speeding up ADP dissociation. Activation of PDC by synthetic PDK inhibitors binding at the pyruvate or lipoyl binding sites decreased damage during heart ischemia and lowered blood glucose in insulin-resistant animals. PDC activation also triggers apoptosis in cancer cells that selectively convert glucose to lactate.

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Anilides of (R)-Trifluoro-2-hydroxy-2-methylpropionic Acid as Inhibitors of Pyruvate Dehydrogenase Kinase

Cited by 59 publications

References 44 publications

Pyruvate dehydrogenase kinase-4 deficiency lowers blood glucose and improves glucose tolerance in diet-induced obese mice

Pyruvate dehydrogenase kinase-4 deficiency lowers blood glucose and improves glucose tolerance in diet-induced obese mice

PDH kinase inhibitors: a novel therapy for Type II diabetes?

Pyruvate dehydrogenase kinase regulatory mechanisms and inhibition in treating diabetes, heart ischemia, and cancer

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