Mechanistic toxicogenomic analysis of WAY-144122 administration in Sprague–Dawley rats

Peterson, Ron L.; Casciotti, Lori; Block, Lutz H.; Goad, Mary E.P.; Zheng, Tong; Meehan, Joshua; Jordan, Ronald A.; Vinlove, M.P; Markiewicz, Victoria; Weed, C.A; Dorner, Andrew J.

doi:10.1016/j.taap.2003.11.016

Cited by 17 publications

(13 citation statements)

References 27 publications

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“…Decreased lipid levels (especially free fatty acids) may be unexpected for a pure PTP1b inhibitor (Klaman et al, 2000). It was more telling, as mentioned above, that rats treated with suprapharmacologic doses of ertiprotafib showed signs of PPAR family activation (peroxisome proliferation, adipose deposition in bone marrow) (Peterson et al, 2004). Because engagement of PPAR family members could contribute to the efficacy seen here, we re-examined the actions of ertiprotafib in vitro to gain a more complete understanding of its mechanism(s) of action.…”

Section: Resultsmentioning

confidence: 93%

“…These animals also exhibited increased liver weights and hepatocellular hypertrophy, along with decreased cholesterol and triglyceride levels. Furthermore, many of the genes with increased liver expression after ertiprotafib treatment are known to be PPAR␣-regulated, including acyl-CoA oxidase, PEX11␣, and CYP4A1 (Peterson et al, 2004). These animals also showed induction of the PPAR␥-regulated gene CD36 in ovaries as well as multiple PPAR␥-dependent genes in fat (R. Peterson, R. Jordan, A. Dorner, unpublished observations).…”

Section: Discussionmentioning

confidence: 98%

“…Thus, given the increase in acyl-CoA oxidase activity in the livers of treated animals, it seems likely that PPAR␣ agonism (in addition to PPAR␥ agonism and PTP1b inhibition) may contribute to the drop in fatty acid levels seen with ertiprotafib treatment, along with a portion of the glucose and insulin lowering. In fact, the livers of Sprague-Dawley rats treated with ertiprotafib showed widespread up-regulation of genes involved in lipid metabolism, peroxisome proliferation, and fatty acid ␤-oxidation (Peterson et al, 2004). These animals also exhibited increased liver weights and hepatocellular hypertrophy, along with decreased cholesterol and triglyceride levels.…”

Section: Discussionmentioning

confidence: 99%

“…It is noteworthy that bone marrow hypocellularity caused by adipocyte deposition was observed in rats treated with suprapharmacologic doses of ertiprotafib, an indication of possible PPAR␥ activation. Furthermore, treated rats showed moderate dose-related increases in liver weights along with ultrastructural signs of peroxisome proliferation, implying potential PPAR␣ activation (Peterson et al, 2004; Z. Tong and J. Scatina, unpublished observations; L. Casciotti and R. Peterson, unpublished observations). These observations prompted the current investigations into the mechanism of action of ertiprotafib.…”

mentioning

confidence: 88%

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Ertiprotafib Improves Glycemic Control and Lowers Lipids via Multiple Mechanisms

Erbe¹,

Wang²,

Zhang³

et al. 2004

Mol Pharmacol

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Ertiprotafib belongs to a novel class of insulin sensitizers developed for treatment of type 2 diabetes. In insulin-resistant rodent models, ertiprotafib and a close analog lowered both fasting blood glucose and insulin levels and improved glycemic excursion during an oral glucose tolerance test. In addition, treatment of rodents improved lipid profiles, with significantly lowered triglyceride and free fatty acid levels. These results suggested that this therapeutic activity might involve mechanisms in addition to PTP1b inhibition. In this study, we demonstrate that ertiprotafib activates peroxisome proliferator-activated receptor (PPAR)␣ and PPAR␥ at concentrations comparable with those of known agonists of these regulators.Furthermore, it is able to drive adipocyte differentiation of C3H10T 1/2 cells, a hallmark of PPAR␥ activation. Livers from ertiprotafib-treated animals showed significant induction of acyl-CoA oxidase activity, probably caused by PPAR␣ engagement in these animals. We also show that ertiprotafib inhibits PTP1b in vitro with nonclassic kinetics at concentrations above its EC 50 for PPAR agonism. Thus, the complete mechanism of action for ertiprotafib and related compounds in vivo may involve multiple independent mechanisms, including (but not necessarily limited to) PTP1b inhibition and dual PPAR␣/ PPAR␥ agonism. Ertiprotafib pharmacology and interpretation of clinical results must be seen in light of this complexity.

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Section: Resultsmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 88%

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Ertiprotafib Improves Glycemic Control and Lowers Lipids via Multiple Mechanisms

Erbe¹,

Wang²,

Zhang³

et al. 2004

Mol Pharmacol

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“…132 Ertiprotafib (60), a mono carboxylic acid benzothiophene phosphotyrosine mimetic discovered at Wyeth as a potent inhibitor of PTP 1B, reached to the clinical trial. 133 The complete mechanism of action for ertiprotafib in vivo involved multiple independent mechanisms, including PTP1B inhibition, dual PPARa/PPARg agonism, and IKK-b inhibition. In the light of this complexity of multiple mechanisms, which could complicate its preclinical efficacy and potentially contribute to its side effects, it was discontinued in Phase II clinical trials.…”

Section: E Benzofuran and Benzothiophene Biphenylsmentioning

confidence: 99%

Protein Tyrosine Phosphatase 1B Inhibitors: A Molecular Level Legitimate Approach for the Management of Diabetes Mellitus

Thareja

Aggarwal

Bhardwaj

et al. 2010

Medicinal Research Reviews

106

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Diabetes mellitus is a systemic disease responsible for morbidity in the western world and is gradually becoming prevalent in developing countries too. The prevalence of diabetes is rapidly increasing in industrialized countries and type 2 diabetes accounts for 90% of the disease. Insulin resistance is a major pathophysiological factor in the development of type 2 diabetes, occurring mainly in muscle, adipose tissues, and liver leading to reduced glucose uptake and utilization and increased glucose production. The prevalence and rising incidence of diabetes emphasized the need to explore new molecular targets and strategies to develop novel antihyperglycemic agents. Protein Tyrosine Phosphatase 1B (PTP 1B) has recently emerged as a promising molecular level legitimate therapeutic target in the effective management of type 2 diabetes. PTP 1B, a cytosolic nonreceptor PTPase, has been implicated as a negative regulator of insulin signal transduction. Therefore, PTP 1B inhibitors would increase insulin sensitivity by blocking the PTP 1B-mediated negative insulin signaling pathway and might be an attractive target for type 2 diabetes mellitus and obesity. With X-ray crystallography and NMR-based fragment screening, the binding interactions of several classes of inhibitors have been elucidated, which could help the design of future PTP 1B inhibitors. The drug discovery research in PTP 1B is a challenging area to work with and many pharmaceutical organizations and academic research laboratories are focusing their research toward the development of potential PTP 1B inhibitors which would prove to be a milestone for the management of diabetes.

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Toxicogenomics and Systems Toxicology

Waters

Fostel

Wetmore

et al. 2006

Computational Toxicology

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Mechanistic toxicogenomic analysis of WAY-144122 administration in Sprague–Dawley rats

Cited by 17 publications

References 27 publications

Ertiprotafib Improves Glycemic Control and Lowers Lipids via Multiple Mechanisms

Ertiprotafib Improves Glycemic Control and Lowers Lipids via Multiple Mechanisms

Protein Tyrosine Phosphatase 1B Inhibitors: A Molecular Level Legitimate Approach for the Management of Diabetes Mellitus

Toxicogenomics and Systems Toxicology

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