Synthesis of tartaric acid analogues of FR258900 and their evaluation as glycogen phosphorylase inhibitors

Structure–Activity Relationships of Glycogen Phosphorylase Inhibitor FR258900 and Its Analogues: A Combined Synthetic, Enzyme Kinetics, and Computational Study

“…Recently, we disclosed our investigations on the synthesis and enzyme kinetic evaluation of several analogues of 1 , in which the core unit was replaced by tartaric acids and the O ‐acyl moieties were also varied. In that study, comparable activities were found for 2,3‐di‐ O ‐feruloyl meso ‐tartaric acid and 1 13…”

“…Previously, we comparatively analyzed the applicability of the above protection strategies for the synthesis of tartaric acid analogues of 1 13. For the orthogonal protection of phenolic OH and COOH groups, methoxycarbonyl and DPM esters, respectively, were found to be the method of choice;14b however, new circumstances had to be developed for the cleavage of the protecting groups 13. The present syntheses of new analogues of 1 were based on these protection group manipulations and gave the desired products without any unexpected synthetic complications.…”

“…Acylations of DPM‐protected hydroxy carboxylic acids 3 and 6 were performed with acid chlorides 7–9 obtained, as described previously,13 in dry toluene with dry pyridine as the catalyst. The desired products 10 – 15 were isolated by column chromatography in moderate to good yields (Scheme , Table 1).…”

“…The kinetic parameters for the synthetic compounds against rabbit muscle glycogen phosphorylase b (RMGP b ) were determined according to a protocol described earlier 22. The results are summarized in Table 4 together with the data for 1 and tartaric acid analogues 47 – 54 13…”

Glycogen phosphorylase inhibitor, 2,3‐bis[(2E)‐3‐(4‐hydroxyphenyl)prop‐2‐enamido] butanedioic acid (BF142), improves baseline insulin secretion of MIN6 insulinoma cells

“…In vivo studies showed that FR258900 significantly reduced blood glucose levels in db/db mice and STZ-induced diabetic mice [ 13 , 14 ]. Tartaric acid-derived GP inhibitors were effective at decreasing rabbit muscle GP activity in the low micromolar range, and are thought to bind to the allosteric site of the GP enzyme [ 15 ]. We investigated the effects of BF142 in the MIN6 cell line, a well-established model for insulin producing β cells.…”