Synthesis And Biological Evaluation Of A Novel PTP1B Inhibitor

Studies performed that the balanced and opposing actions of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPases) regulated the physiological tyrosine phosphorylation levels of proteins. Protein tyrosine phosphatase 1B (PTP1B) is a member of superfamily of PTPases. Correlational studies displayd that the PTP1B had antagonistic effect to insulin and leptin signaling pathways. So PTP1B has been developed as potential therapeutic agents in treating Type II diabetes and obesity since it was discovered. Because of bad selectivity over PTPs and the low bioavailability, there were only two small molecule compounds entering clinical trials. So it is promising to develop potent PTP1B-specific inhibitor.PTP1B includes a catalytic site which is homology to other PTPases and a non-catalytic phosphotyrosine binding site (site 2). Basing on investigation of recent published papers, we found that an effective PTP1B inhibitor may require a combination of three moieties:a hydrophilic head, an aromatic center and a hydrophobic. According to the successful designing structure of C, we designed two new target compound 1 and 2. The compound 1 and 2 were achieved through eleven steps with Negishi cross-coupling reaction, diastereoselective sulfinylimine enolate addition reaction and the Dess-Martin oxidation as key steps. The compound 1 inhibited PTP1B competitively with an IC50 value of 54.17 μM in vitro, and the compound 2 was 68.22 μM.To clerity the potency of the synthesized compounds and guide further structure-activity relationships (SARs) studies, compounds 1 and 2 were docked into the active site of PTP1B.The docking results revealed that diaryl oxamic acid phenylacetamide group of 1 binded to the catalytic site and six hydrogen bonds were formed. The compound 1 and PTP1B formed three hydrogen bonds adjacent to the catalytic site. The diaryl oxamic acid acetamidothiazole group of 2 formed five hydrogen bonds with the catalytic site. It also formed three hydrogen bonds with PTP1B near the catalytic site. The pentylamide group of 1 and 2 extended to the non-catalytic binding site.