Bioorganic and Medicinal Chemistry p. 3670 - 3683 (2014)
Update date:2022-08-04
Topics:
Zhi, Ying
Gao, Li-Xin
Jin, Yi
Tang, Chun-Lan
Li, Jing-Ya
Li, Jia
Long, Ya-Qiu
Protein tyrosine phosphatase 1B is a negative regulator in the insulin and leptin signaling pathways, and has emerged as an attractive target for the treatment of type 2 diabetes and obesity. However, the essential pharmacophore of charged phosphotyrosine or its mimetic confer low selectivity and poor cell permeability. Starting from our previously reported aryl diketoacid-based PTP1B inhibitors, a drug-like scaffold of 4-quinolone-3-carboxylic acid was introduced for the first time as a novel surrogate of phosphotyrosine. An optimal combination of hydrophobic groups installed at C-6, N-1 and C-3 positions of the quinolone motif afforded potent PTP1B inhibitors with low micromolar IC 50 values. These 4-quinolone-3-carboxylate based PTP1B inhibitors displayed a 2-10 fold selectivity over a panel of PTP's. Furthermore, the bidentate inhibitors of 4-quinolone-3-carboxylic acids conjugated with aryl diketoacid or salicylic acid were cell permeable and enhanced insulin signaling in CHO/hIR cells. The kinetic studies and molecular modeling suggest that the 4-quinolone-3-carboxylates act as competitive inhibitors by binding to the PTP1B active site in the WPD loop closed conformation. Taken together, our study shows that the 4-quinolone-3-carboxylic acid derivatives exhibit improved pharmacological properties over previously described PTB1B inhibitors and warrant further preclinical studies.
View MoreContact:+86-0512-69209969
Address:Room 317,Lushan Road,Suzhou New District,Jiangsu Province,China.
Wuhan Kemi-Works Chemical Co., Ltd
website:http://www.kemiworks.com
Contact:86-27-85736489
Address:Rm. 1503, No. 164, Jianghan North Rd., Wuhan, 430022 China
Contact:+33-5-34012600
Address:28 ZA des Pignès
Contact:+86-571-86491666
Address:SHI XIANG ROAD
Ningbo Inno Pharmchem Co., Ltd.
Contact:86-574-87319282
Address:6F-5,NO.163 RUIQING RD.,NINGBO 315000 CHINA
Doi:10.1021/ja505446y
(2014)Doi:10.1021/om500438s
(2014)Doi:10.1016/0022-328X(94)00009-2
(1995)Doi:10.1016/j.ejmech.2014.04.057
(2014)Doi:10.1021/acs.orglett.1c00834
(2021)Doi:10.1021/jo00104a053
(1994)