European Journal of Medicinal Chemistry p. 178 - 185 (2019)
Update date:2022-09-26
Topics:
Li, Xiangqian
Xu, Qi
Li, Chao
Luo, Jiao
Li, Xiuxue
Wang, Lijun
Jiang, Bo
Shi, Dayong
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.
View MoreNaturalin Bio-Resource Co., Ltd
website:http://www.naturalin.com
Contact:+86-0731-84430651
Address:B1-402, Lu-Valley Enterprise Square.No.27 Wenxuan Road. Lu-Valley Hi-Tech District.
Contact:0086 371 65711996
Address:Jalan 4/3, Kawasan Perindustrian Serendah, 48000 Rawang,
Zhuzhou Farshine Chemical Industry Co., Ltd
Contact:0086-731-28482786
Address:No. 1,Shui Xian Road, He Tang Dictrict,Hunan-412000,China
Contact:+86-532-80762375
Address:No. 6, Hongkong Middle Road, Qingdao, China
Shanghai Haoyuan Chemexpress Co., Ltd.
Contact:86-21-51870955;58998985;58999585
Address:Room 601, No. 2 BLD, NO. 720, Cailun Road, Zhangjiang, Shanghai, China
Doi:10.1002/chem.201202601
(2013)Doi:10.1016/j.tetlet.2013.04.066
(2013)Doi:10.1016/S0040-4039(00)61241-8
(1992)Doi:10.1055/s-0032-1318345
(2013)Doi:10.1016/S0040-4039(00)61295-9
(1992)Doi:10.1016/j.tet.2013.06.012
(2013)