Toward a treatment of diabesity: In vitro and in vivo evaluation of uncharged bromophenol derivatives as a new series of PTP1B inhibitors.

Abstract

Protein tyrosine phosphatase 1B (PTP1B) has been considered as a validated biological target for type 2 diabetes treatment, but past endeavors to develop inhibitors of PTP1B into drugs have been unsuccessful. Two challenging aspects are selective inhibition and cell permeability. A structure-based strategy was employed to develop uncharged bromophenols as a new series of PTP1B inhibitors. The most potent compound 22 (LXQ46) inhibited PTP1B with an IC50 value of 0.190 μM, and showed remarkable selectivity over other protein tyrosine phosphatases (PTPs, 20-200 folds). In the SPR study, increasing concentrations of compound 22 led to concentration-dependent increases in binding responses, indicating that compound 22 could bind to the surface of PTP1B via noncovalent means. By treating insulin-resistant C2C12 myotubes with compound 22, enhanced insulin and leptin signaling pathways were observed. Long-term oral administration of compound 22 reduced the blood glucose level of diabetic BKS db mice. The glucose tolerance tests (OGTT) and insulin tolerance tests (ITT) in BKS db mice showed that oral administration of compound 22 could increase insulin sensitivity. In addition, long-term oral administration of compound 22 could protect mice from obesity, which was not the result of toxicity. Our pharmacokinetics results from the rat-based assays showed that orally administered compound 22 was absorbed rapidly from the gastrointestinal tract, extensively distributed to the tissues, and rapidly eliminated from the body. All these results indicate that compound 22 could serve as a qualified agent to treat type II diabetes.

• Authors: Xiangqian Li, Qi Xu, Chao Li, Jiao Luo, Xiuxue Li, Lijun Wang, Bo Jiang, Dayong Shi
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 166 Pg. 178-185 (Mar 15 2019) ISSN: 1768-3254 [Electronic] France
• PMID: 30711829 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier Masson SAS. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Insulin
• Leptin
• Phenols
• Proto-Oncogene Proteins c-akt
• Protein Tyrosine Phosphatase, Non-Receptor Type 1

Topics

• Animals
• Body Weight (drug effects)
• Cell Line
• Diabetes Mellitus, Type 2 (complications, drug therapy, metabolism, pathology)
• Drug Evaluation, Preclinical
• Enzyme Inhibitors (chemistry, pharmacokinetics, pharmacology, therapeutic use)
• Insulin (metabolism)
• Insulin Resistance
• Leptin (metabolism)
• Mice
• Molecular Docking Simulation
• Obesity (complications)
• Phenols (chemistry, pharmacokinetics, pharmacology, therapeutic use)
• Phosphorylation (drug effects)
• Protein Conformation
• Protein Tyrosine Phosphatase, Non-Receptor Type 1 (antagonists & inhibitors, chemistry, metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Safety
• Signal Transduction (drug effects)