PTP1B inhibitor Ertiprotafib is also a potent inhibitor of IκB kinase β (IKK-β)

Shrestha, Suja; Bhattarai, Bharat Raj; Cho, Heeyeong; Choi, Jong Soo; Cho, Hyeongjin

doi:10.1016/j.bmcl.2007.03.001

Cited by 42 publications

(26 citation statements)

References 18 publications

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“…Ertiprotafib (Wyeth Pharmaceuticals; acquired by Pfizer) showed initial promise by lowering blood glucose levels when orally administered to mice 48 and progressed to a phase II clinical trial. Further studies also indicated decreased insulin levels, along with lowered triglyceride and free fatty acid levels; however, these outcomes were reported to be likely due to off-target effects of ertiprotafib, which include activation of peroxisome proliferator-activated receptor α (PPARα) and PPARγ 49 , and potent inhibition of IκB kinase β (IKK-β) 50 . Phase II trials with ertiprotafib were discontinued, likely due to its lack of in vivo efficacy, coupled with unwanted side effects 49 .…”

Section: Strategies To Modulate Liver Glucose and Glycogen Metabolismmentioning

confidence: 99%

Targeting hepatic glucose metabolism in the treatment of type 2 diabetes

Rines

Sharabi

Tavares

et al. 2016

Nat Rev Drug Discov

295

244

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Type 2 diabetes mellitus is characterized by the dysregulation of glucose homeostasis resulting in hyperglycemia. Although current diabetes treatments have exhibited some success in lowering blood glucose, their effect is not always sustained and their use may be associated with undesirable side effects, such as hypoglycemia. Novel diabetic drugs, which may be used in combination with existing therapies, are therefore needed. The potential of specifically targeting the liver in order to normalize blood glucose levels has not been fully exploited. Here, we review the molecular mechanisms controlling hepatic gluconeogenesis and glycogen storage, and assess the prospect of therapeutically targeting associated pathways to treat type 2 diabetes.

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Section: Strategies To Modulate Liver Glucose and Glycogen Metabolismmentioning

confidence: 99%

Targeting hepatic glucose metabolism in the treatment of type 2 diabetes

Rines

Sharabi

Tavares

et al. 2016

Nat Rev Drug Discov

295

244

View full text Add to dashboard Cite

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“…In addition, Ertiprotafib was shown to be a potent inhibitor of IkB kinase b, with an IC 50 of 400 nM. 165 Hence it is easy to interpret the failed clinical trials in light of these complexities.…”

Section: Clinical Development Of Ptp1b Inhibitorsmentioning

confidence: 99%

“…168 Another molecule is Trodusquemine (MSI-1436, 104), a drug candidate discovered by Genaera for the treatment of type 2 diabetes and obesity. 139,165,169 It is a reversible, allosteric, noncompetitive, and highly selective inhibitor of PTP1B that significantly enhanced insulin-stimulated tyrosine phosphorylation of IR and STAT3, substrates of PTP1B, in HepG2 cells and/or hypothalamic tissue. By inhibiting PTP1B, Trodusquemine decreased appetite, caused weight loss without metabolic rebound, and normalized both fasting blood glucose, blood cholesterol, and triglyceride levels in obese animal models.…”

Section: Clinical Development Of Ptp1b Inhibitorsmentioning

confidence: 99%

Chapter 6. Recent Advances in PTP1B Inhibitor Development for the Treatment of Type 2 Diabetes and Obesity

He¹,

Zeng²,

He³

et al. 2012

Drug Discovery

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“…In this study we used different scoring functions available in FlexX module. Totally 40(7.40%) active compounds that have IC 50 value ranges from 8 nM to 1500 nM were collected from the literature 2,5,7,9,10,[30][31][32][33][34][35][36][37] and randomly chose 500 (92.60%) ChemDiv 38 GPCR focused library compounds that were used as decoys. FlexX-Pharm was used to define pharmacophore constraints, hinge region Cys99 donor mentioned as an optional constraint.…”

Section: Scoring Function Identificationmentioning

confidence: 99%