The difluoromethylenesulfonic acid group as a monoanionic phosphate surrogate for obtaining PTP1B inhibitors Original Research Article

Three peptides, 7–9, bearing sulfono(difluoromethyl)phenylalanine (F2Smp, 2), a nonhydrolyzable, monoanionic phosphotyrosine mimetic, were prepared and evaluated as PTP1B inhibitors. The most effective inhibitor was the nonapeptide, ELEF(F2Smp)MDYE-NH2, (9) which exhibited a Ki of 360 nM. A comparison of F2Smp-bearing peptides 7 [DADE(F2Smp)LNH2, Ki=3.4 μM] and 8 [EEDE(F2Smp)LNH2, Ki=0.74 μM] with their phosphono(difluoromethyl)phenylalanine (F2Pmp)-bearing analogues indicated that F2Smp is not as effective a pTyr mimetic as F2Pmp by 100- to 130-fold. Although F2Smp is not as effective as F2Pmp, a comparison of peptide 7 with analagous peptides bearing other monoanionic pTyr mimetics recently reported in the literature indicates that F2Smp is about 65-fold more effective than any other non-hydrolyzable, monanionic pTyr mimetic reported to date. To further assess the difluoromethylenesulfonic acid (DFMS) group as a monoanionic phosphate mimetic, a series of 24 nonpeptidyl biaryl compounds bearing the DFMS group were prepared using polymer-supported methodologies and screened for PTP1B inhibition. Several of these compounds were selected for further study and their IC50ʹs compared to their difluoromethylenephosphonic (DFMP) analogues. The differences in IC50ʹs between the DFMS and DFMP non-peptidyl compounds was not as great as with the F2Smp- and F2Pmp-bearing peptides. Possible reasons for this and its implication to the design of small molecule PTP1B inhibitors is discussed.