1H-2,3-Dihydroperimidine Derivatives: A New Class of Potent Protein Tyrosine Phosphatase 1B Inhibitors

Abstract

A series of 1H-2,3-dihydroperimidine derivatives was designed, synthesized, and evaluated as a new class of inhibitors of protein tyrosine phosphatase 1B (PTP1B) with IC 50 values in the micromolar range. Compounds 46 and 49 showed submicromolar inhibitory activity against PTP1B, and good selectivity (3.48-fold and 2.10-fold respectively) over T-cell protein tyrosine phosphatases (TCPTP). These results have provided novel lead compounds for the design of inhibitors of PTP1B as well as other PTPs.

Synthesis of Novel 3‐aryl‐1‐oxa‐2,8‐diazaspiro[4.5]dec‐2‐ene Derivatives and Their Biological Evaluation Against Protein Tyrosine Phosphatase 1B

“…To study the inhibition on the other PTPase family members, SHP1, SHP2, and LAR were prepared and assays were performed according to the procedures described previously (14,18). Briefly, the enzymatic activities of the SHP1, SHP2, and LAR were determined at 30°C by monitoring the dephosphorylation of the substrate 3-omethylfluorescein phosphate (OMFP), and the product was then detected at a 485 nm excitation wavelength and 530 nm emission wavelength by the EnVision multilabel plate reader (Perkin-Elmer Life Sciences, Boston, MA, USA).…”

“…Homogeneous T-cell protein tyrosine phosphatase (TCPTP) inhibitory activities were investigated simultaneously by the same method (14,18). Compound 6f showed 42.2% inhibition at the concentration of 20 lg/mL (31.35 lM), and the result indicated that compound 6f had greater selectivity for PTP1B than for TCPTP.…”

“…The inhibitory activities of all synthesized compounds against PTP1B were measured using p-nitrophenyl phos- phate (pNPP) as the substrate (14,18), and the results are detailed in Table 3. As for compounds 4a-4e, compound 4a, which has unsubstituted phenyl group, exhibited slightly better inhibitory activity than compounds 4b-4d, which have electron-donating substitutes at the para position of the phenyl ring, while compound 4e, which has electron-withdrawing group (Br), showed slightly better inhibitory activity than compound 4a.…”

“…Previously, we identified 1H-2,3-dihydroperimidine derivatives as potent PTP1B inhibitors (14). To explore the structural diversity of PTP1B inhibitors, our initial approach was to adjust the conformation between aryl ring and hydroprimidine ring, using conformational restriction strategy to replace aryl-dihydroprimidine unit with 1-oxa-2,8-diazaspiro [4.5]dec-2-ene unit (Figure 1), and synthesize tert-butyl 3-aryl-1-oxa-2,8-diazaspiro [4.5]dec-2-ene-8-carboxylates and their derivatives for biological evaluation against PTP1B.…”

Design, Synthesis and Biological Evaluation of Stilbene Derivatives as Novel Inhibitors of Protein Tyrosine Phosphatase 1B

“…Moreover, it is worth noting that PTPs share a high degree of structural conservation in the active site, especially for T-cell protein tyrosine phosphatase (TCPTP), which has a sequence identity of about 74% in the catalytic domains with PTP1B [9]. There is always a challenge for the potent PTP1B inhibitors to keep good selectivity over TCPTP in the same time [10].…”