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Biomedical subjects

Denise Wilcox

Publications and source records attributed to Denise Wilcox.

11 recordsLinked to original sources
PubMed2006

Parallel strategies for the preparation and selection of liver-targeted glucocorticoid receptor antagonists.

Libraries of mifepristone analogs, MP-Acids, were designed and synthesized to increase the chances of identifying GR antagonists that possess liver-selective pharmacological profiles. MP-Acids were uniformly potent GR antagonists in binding and in cell-based functional assays. A high throughput pharmacokinetic selection strategy that employs the cassette dosing of MP-Acids was developed to identify liver-targeting compounds. Thus, resource-intensive in vivo assays to measure liver-selective pharmacology were enriched with GR antagonists that achieve high concentrations in the liver.

Animals↗
PubMed2006

Discovery of orally active butyrolactam 11beta-HSD1 inhibitors.

A series of metabolically stable butyrolactam 11beta-HSD1 inhibitors have been synthesized and biologically evaluated. These compounds exhibit excellent HSD1 potency and HSD2 selectivity, pharmacokinetic, and pharmacodynamic profiles.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2006

Hepatic knockdown of mitochondrial GPAT1 in ob/ob mice improves metabolic profile.

Glycerol-3-phosphate acyltransferase (GPAT) controls the first step of triglyceride (TAG) synthesis. Three distinct GPAT activities have been identified, two localized in mitochondria and one in microsomes. Mitochondrial GPAT1 (mtGPAT1) is abundantly expressed in the liver and constitutes approximately 50% of total GPAT activities in this organ. Hepatic mtGPAT1 activity is elevated in obese rodents. Mice deficient in mtGPAT1 have an improved lipid profile. To investigate if beneficial effects can result from reduced hepatic expression of mtGPAT1 in adult obese mice, adenoviral vector-based short hairpin RNA interference (shRNA) technology was used to knockdown mtGPAT1 expression in livers of ob/ob mice. Reduced expression of mtGPAT1 mRNA in liver of ob/ob mice resulted in dramatic and dose dependent reduction in mtGPAT1 activity. Reduced hepatic TAG, diacylglycerol, and free fatty acid, as well as reduced plasma cholesterol and glucose, were also observed. Fatty acid composition analysis revealed decrease of C16:0 in major lipid species. Our results demonstrate that acute reduction of mtGPAT1 in liver of ob/ob mice reduces TAG synthesis, which points to a role for mtGPAT1 in the correction of obesity and related disorders.

Adenoviridae↗
PubMed2005

Rapamycin analogs with reduced systemic exposure.

The synthesis and biological activities of rapamycin (I) analogs modified at the C-40 position are reported. Emphasis placed on compounds that potentially have an improved safety profile on account of their shorter in vivo half-life when compared with rapamycin.

Animals↗
PubMed2005

Antidiabetic activity of passive nonsteroidal glucocorticoid receptor modulators.

Much has been learned about the consequences of glucocorticoid receptor antagonism by studying steroidal active antagonists such as RU-38486 (1). In the liver glucocorticoid receptor antagonism suppresses hepatic glucose production decreasing plasma glucose levels; however, extrahepatic antagonism produces several undesirable side effects including activation of the hypothalamic pituitary adrenal axis. A series of nonsteroidal passive N-(3-dibenzylamino-2-alkyl-phenyl)-methanesulfonamide glucocorticoid receptor modulators was discovered. Liver selective and systemically available members of this series were found and characterized in diabetes and side effect rodent models. A highly liver selective member of this series, acid 14, shows efficacy in the ob/ob model of diabetes. It lowers plasma glucose, cholesterol, and free fatty acid concentrations and reduces the rate of body weight gain. The structurally related systemically available passive modulator 12 lowers glucose, HbA(1c), triglyceride, free fatty acid, and cholesterol levels. Interestingly, it did not acutely activate the hypothalamic pituitary adrenal axis in unstressed CD-1 mice or have the abortive effects observed with 1. These results indicate that passive GR antagonists may have utility as antidiabetic agents.

Alkaline Phosphatase↗
PubMed2005

Hepatic glucocorticoid receptor antagonism is sufficient to reduce elevated hepatic glucose output and improve glucose control in animal models of type 2 diabetes.

Glucocorticoids amplify endogenous glucose production in type 2 diabetes by increasing hepatic glucose output. Systemic glucocorticoid blockade lowers glucose levels in type 2 diabetes, but with several adverse consequences. It has been proposed, but never demonstrated, that a liver-selective glucocorticoid receptor antagonist (LSGRA) would be sufficient to reduce hepatic glucose output (HGO) and restore glucose control to type 2 diabetic patients with minimal systemic side effects. A-348441 [(3b,5b,7a,12a)-7,12-dihydroxy-3-{2-[{4-[(11b,17b)-17-hydroxy-3-oxo-17-prop-1-ynylestra-4,9-dien-11-yl] phenyl}(methyl)amino]ethoxy}cholan-24-oic acid] represents the first LSGRA with significant antidiabetic activity. A-348441 antagonizes glucocorticoid-up-regulated hepatic genes, normalizes postprandial glucose in diabetic mice, and demonstrates synergistic effects on blood glucose in these animals when coadministered with an insulin sensitizer. In insulin-resistant Zucker fa/fa rats and fasted conscious normal dogs, A-348441 reduces HGO with no acute effect on peripheral glucose uptake. A-348441 has no effect on the hypothalamic pituitary adrenal axis or on other measured glucocorticoid-induced extrahepatic responses. Overall, A-348441 demonstrates that an LSGRA is sufficient to reduce elevated HGO and normalize blood glucose and may provide a new therapeutic approach for the treatment of type 2 diabetes.

3T3 Cells↗
PubMed2004

Liver-selective glucocorticoid antagonists: a novel treatment for type 2 diabetes.

Hepatic blockade of glucocorticoid receptors (GR) suppresses glucose production and thus decreases circulating glucose levels, but systemic glucocorticoid antagonism can produce adrenal insufficiency and other undesirable side effects. These hepatic and systemic responses might be dissected, leading to liver-selective pharmacology, when a GR antagonist is linked to a bile acid in an appropriate manner. Bile acid conjugation can be accomplished with a minimal loss of binding affinity for GR. The resultant conjugates remain potent in cell-based functional assays. A novel in vivo assay has been developed to simultaneously evaluate both hepatic and systemic GR blockade; this assay has been used to optimize the nature and site of the linker functionality, as well as the choice of the GR antagonist and the bile acid. This optimization led to the identification of A-348441, which reduces glucose levels and improves lipid profiles in an animal model of diabetes.

Animals↗
PubMed2004

ABT-963 [2-(3,4-difluoro-phenyl)-4-(3-hydroxy-3-methyl-butoxy)-5-(4-methanesulfonyl-phenyl)-2H-pyridazin-3-one], a highly potent and selective disubstituted pyridazinone cyclooxgenase-2 inhibitor.

Nonsteriodal anti-inflammatory drugs (NSAIDs) are efficacious for the treatment of pain associated with inflammatory disease. Clinical experience with marketed selective cyclooxygenase-2 (COX-2) inhibitors (celecoxib, rofecoxib, and valdecoxib) has confirmed the utility of these agents in the treatment of inflammatory pain with an improved gastrointestinal safety profile relative to NSAID comparators. These COX-2 inhibitors belong to the same structural class. Each contains a core heterocyclic ring with two appropriately substituted phenyl rings appended to adjacent atoms. Here, we report the identification of vicinally disubstituted pyridazinones as potent and selective COX-2 inhibitors. The lead compound in the series, ABT-963 [2-(3,4-difluoro-phenyl)-4-(3-hydroxy-3-methyl-butoxy)-5-(4-methanesulfonyl-phenyl)-2H-pyridazin-3-one], has excellent selectivity (ratio of 276, COX-2/COX-1) in human whole blood, improved aqueous solubility compared with celecoxib and rofecoxib, high oral anti-inflammatory potency in vivo, and gastric safety in the animal studies. After oral administration, ABT-963 reduced prostaglandin E2 production in the rat carrageenan air pouch model (ED50 of 0.4 mg/kg) and reduced the edema in the carrageenan induced paw edema model with an ED30 of 1.9 mg/kg. ABT-963 dose dependently reduced nociception in the carrageenan hyperalgesia model (ED50 of 3.1 mg/kg). After 14 days of dosing in the adjuvant arthritis model, ABT-963 had an ED(50) of 1.0 mg/kg in reducing the swelling of the hind paws. Magnetic resonance imaging examination of the diseased paws in the adjuvant model showed that ABT-963 significantly reduced bone loss and soft tissue destruction. ABT-963 is a highly selective COX-2 inhibitor that may have utility in the treatment of the pain and inflammation associated with arthritis.

Animals↗
PubMed2003

Antisense protein tyrosine phosphatase 1B reverses activation of p38 mitogen-activated protein kinase in liver of ob/ob mice.

Phosphorylation of stress-activated kinase p38, a MAPK family member, was increased in liver of ob/ob diabetic mice relative to lean littermates. Treatment of ob/ob mice with protein tyrosine phosphatase 1B (PTP1B) antisense oligonucleotides (ASO) reduced phosphorylation of p38 in liver-to below lean littermate levels-and normalized plasma glucose while reducing plasma insulin. Phosphorylation of ERK, but not JNK, was also decreased in ASO-treated mice. PTP1B ASO decreased TNFalpha protein levels and phosphorylation of the transcription factor cAMP response element binding protein (CREB) in liver, both of which can occur through decreased phosphorylation of p38 and both of which have been implicated in insulin resistance or hyperglycemia. Decreased p38 phosphorylation was not directly due to decreased phosphorylation of the kinases that normally phosphorylate p38-MKK3 and MKK6. Additionally, p38 phosphorylation was not enhanced in liver upon insulin stimulation of ASO-treated ob/ob mice (despite increased activation of other signaling molecules) corroborating that p38 is not directly affected via the insulin receptor. Instead, decreased phosphorylation of p38 may be due to increased expression of MAPK phosphatases, particularly the p38/ERK phosphatase PAC1 (phosphatase of activated cells). This study demonstrates that reduction of PTP1B protein using ASO reduces activation of p38 and its substrates TNFalpha and CREB in liver of diabetic mice, which correlates with decreased hyperglycemia and hyperinsulinemia.

Animals↗
PubMed2002

PTP1B antisense oligonucleotide lowers PTP1B protein, normalizes blood glucose, and improves insulin sensitivity in diabetic mice.

The role of protein-tyrosine phosphatase 1B (PTP1B) in diabetes was investigated using an antisense oligonucleotide in ob/ob and db/db mice. PTP1B antisense oligonucleotide treatment normalized plasma glucose levels, postprandial glucose excursion, and HbA(1C). Hyperinsulinemia was also reduced with improved insulin sensitivity. PTP1B protein and mRNA were reduced in liver and fat with no effect in skeletal muscle. Insulin signaling proteins, insulin receptor substrate 2 and phosphatidylinositol 3 (PI3)-kinase regulatory subunit p50alpha, were increased and PI3-kinase p85alpha expression was decreased in liver and fat. These changes in protein expression correlated with increased insulin-stimulated protein kinase B phosphorylation. The expression of liver gluconeogenic enzymes, phosphoenolpyruvate carboxykinase, and fructose-1,6-bisphosphatase was also down-regulated. These findings suggest that PTP1B modulates insulin signaling in liver and fat, and that therapeutic modalities targeting PTP1B inhibition may have clinical benefit in type 2 diabetes.

Adipose Tissue↗