(<i>R</i>)-3,3,3-Trifluoro-2-hydroxy-2-methylpropionamides Are Orally Active Inhibitors of Pyruvate Dehydrogenase Kinase

Aicher, Thomas D.; Anderson, Robert C.; Bebernitz, Gregory R.; Coppola, Gary M.; Jewell, Charles; Knorr, Douglas C.; Liu, C.; Sperbeck, Donald M.; Brand, Leonard; Strohschein, Robert J.; Gao, Jianping; Vinluan, Christine C.; Shetty, Suraj S.; Dragland, Carol J.; Kaplan, Emma L.; DelGrande, Dominick; Islam, Asimul; Li, Xilin; Lozito, Robert J.; Maniara, Wieslawa; Walter, R.Erik; Mann, W.

doi:10.1021/jm9902584

Cited by 50 publications

(32 citation statements)

References 47 publications

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“…Aicher et al [2] reported a series of compounds which activate PDH in vitro and decrease lactate in vivo; one of these, identified as 'Novartis 3r', has proved to be of particular interest in evaluating in vivo efficacy. We described AZD7545 and related compounds [3,4], which have structural similarities to those described by Aicher et al [2]. Further exploration of the in vitro selectivity…”

Section: Introductionmentioning

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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Section: Introductionmentioning

confidence: 99%

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

Mayers

Leighton

Kilgour

2005

Biochemical Society Transactions

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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%

“…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]. As indicated above, recent studies have established that Nov3r and related inhibitors bind tightly to PDK2 at the site of binding of the lipoyl prosthetic group of the L2 domain [64].…”

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].…”

mentioning

confidence: 99%

“…Roche and Y. Hiromasa Pyruvate dehydrogenase kinase molecular mechanisms of the L2 domain[63,64]; Nov3r (see structure,Fig. 5, below) and related inhibitors[123][124][125][126] prevent binding of PDK2 to L2 or E2. PDK2 bind much tighter to the dimeric GST-L2 structure than the L2 monomer, supporting bifunctional binding of PDK2 to two L2 domains…”

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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.

234

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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Applications of Nitrile Hydratases and Nitrilases

DeSantis

DiCosimo

2009

Biocatalysis for the Pharmaceutical Industry

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(R)-3,3,3-Trifluoro-2-hydroxy-2-methylpropionamides Are Orally Active Inhibitors of Pyruvate Dehydrogenase Kinase

Cited by 50 publications

References 47 publications

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

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

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

Applications of Nitrile Hydratases and Nitrilases

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