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

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

  • Eur J Med Chem. 2019 Mar 15:166:178-185. doi: 10.1016/j.ejmech.2019.01.057.
Xiangqian Li 1 Qi Xu 2 Chao Li 2 Jiao Luo 2 Xiuxue Li 2 Lijun Wang 1 Bo Jiang 1 Dayong Shi 3
Affiliations

Affiliations

  • 1 Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China; Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.
  • 2 Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China.
  • 3 State Key Laboratory of Microbial Technology, Shandong University, Qingdao, China. Electronic address: shidayong@qdio.ac.cn.
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.

Keywords

Anti-diabetic; BKS db mice; PTP1B inhibitor; Selectivity; Toxicity.

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