Anti-type ¢ò Diabetes Novel Ptp-1b Inhibitor Design, Synthesis, And Its Activity

Protein tyrosine phosphatase 1B (PTP-1B) has been implicated as one of the key negative regulators of insulin and leptin signal transduction pathways. Recent knock-out studies and anti-sense oligonucleotide (ASO) treatment in mice have identified PTP-1B as a potential target for chemotherapy of diabetes and obesity. Therefore, inhibiting PTP-1B with small molecules represents a novel therapeutic approach for insulin resistance, type II diabetes, and obesity.This thesis reports the design, synthesis and evaluation of a novel series of PTP-1B inhibitors. The accomplished research work is highlighted as follows:After the analysis of crystal structures of PTP-1B complexed with the substrate (or known potent inhibitors), the binding mode of the inhibitors and PTP-1B were proposed and the pharmacophore of the inhibitors was summarized. 9 series of target compounds were designed and synthesized as novel inhibitors of PTP-1B according to the obtained pharmacophore model.30 target compounds which are not reported in the literature were synthesized and their structures were identified by ~1HNMR and MS (EI, FAB or ESI). Moreover 58 key intermediates were prepared and characterized by ~1H-NMR, among which 31 compounds were not reported in the literature.Most of the target compounds were evaluated in vitro. Some of the compounds (LDY-4-7, LDY-4-23, and LDY-5-19) showed inhibitory activity against human recombinant PTP-1B. The acquirement of these moderately active compounds, as well as the feedback got from the design-synthesis-evaluation iteration will benefit further design and synthesis of new compounds.