Discovery and Structure-activity Relationships of Tetrahydro-3H-cyclopenta[c]quinolines Scaffold-based Potential PTP1B Inhibitors
CHAI Qian, SHEN Qiang, MA Lan-Ping*, WANG Xin, MENG Tao, LI Jing-Ya, LI Jia, SHEN Jing-Kang
2011, 32(2):
306-315.
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The protein tyrosine phosphatases (PTPs) constitute a family of closely related key regulatory enzymes that dephosphorylate phosphotyrosine residues in their protein substrates. Malfunctions in PTP activity are linked to various diseases, ranging from cancer to neurological disorders and diabetes. As part of a project aimed at identifying small molecular inhibitors based on PTPs family, focusing on diabetes mellitus, tumorigenesis, and infection, we performed the High-throughput Screening(HTS) of a library of 48,000 synthetic compounds for six representative PTPs, including PTP1B, SHP1, SHP2, PRL3, CDC25B and LAR, and 3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline analogues were identified as PTPs inhibitors. Keeping the core template complete, we begin the modification of benzene ring, intending to find out the best modifying position in benzene ring and the proper amount of substitutions on it. Consequently, thirty-four compounds have been designed and synthesized, and careful SAR study with respect to PTP1B, SHP1, SHP2, PRL3, CDC25B and LAR was carried out. Finally, it has been found that the compounds bearing a bulky substituent at 8-position of the cyclopentaquinoline acid turned out to be PTP1B inhibitors with good potency and selectivity against other assayed PTPs. The most potent PTP1B inhibitor in this series, compound 31 and 35, showed good activity (IC50=0.4μmol/L and 0.6μmol/L, respectively) and excellent selectivity for PTP1B over SHP1, SHP2, PRL3 and LAR, and 30-fold selectivity over CDC25B. Due to time limit, the modification of core template is not sufficient enough, and it would be the direction of our further work to discover more potent core structures.
