Probing acid replacements of thiophene PTP1B inhibitors

The following account describes our systematic effort to replace one of the carboxylate groups of our diacid thiophene PTP1B inhibitors. Active hits were validated using enzymatic assays before pursuing efforts to improve the potency. Only when the C2 carboxylic acid was replaced with another ionizable functional group was reversible and competitive inhibition retained. Use of a tetrazole ring or 1,2,5-thiadiazolidine-3-one-1,1-dioxide as a carboxylate mimetic led to the discovery of two unique starting series that showed improved permeability (PAMPA) and potency of the order of 300 nM. The SAR from these efforts underscores some of the major challenges in developing small molecule inhibitors for PTP1B.

Graphical abstractA series of acid replacement groups were prepared and evaluated as PTP1B inhibitors. 2-Tetrazole and 3-thiourea were identified as potential acid replacement groups that display improved permeability versus our diacid thiophene lead compound.Figure optionsDownload full-size imageDownload as PowerPoint slide