Ertiprotafib Improves Glycemic Control and Lowers Lipids via Multiple Mechanisms

Abstract

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.

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

“…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. 134 136 Vanadate and pervanadate (the complexes of vanadate with hydrogen peroxide) are two commonly used general PTP inhibitors. These compounds also have insulin-mimetic properties, an observation that has generated a great deal of interest.…”

Targeting hepatic glucose metabolism in the treatment of type 2 diabetes

“…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 .…”

1H-2,3-Dihydroperimidine Derivatives: A New Class of Potent Protein Tyrosine Phosphatase 1B Inhibitors

“…Yield = 42%, mp 233.1-234.3 °C; (17). Yield = 55%, mp 99.7-103.3 °C; (18). Yield = 47%, mp 102.8-107.4 °C; (19).…”

“…A variety of PTP1B inhibitors have been disclosed among academic and industrial laboratories [15][16][17]. Two compounds, ertiprotafib and trodusquemine, have progressed to clinical trials [18,19]. However, ertiprotafib was discontinued in phase II clinical trials due to a lack of efficacy and side effects [20].…”