Probing acid replacements of thiophene PTP1B inhibitors.

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Wan ZK, Follows B, Kirincich S, Wilson D, Binnun E, Xu W, Joseph-McCarthy D, Wu J, Smith M, Zhang YL, Tam M, Erbe D, Tam S, Saiah E, Lee J

Probing acid replacements of thiophene PTP1B inhibitors.

Bioorg Med Chem Lett. 2007 May 15;17(10):2913-20. Epub 2007 Feb 20.

PubMed ID

17336064 [ View in PubMed

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Abstract

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 300nM. The SAR from these efforts underscores some of the major challenges in developing small molecule inhibitors for PTP1B.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
5-(4-CHLORO-5-PHENYL-3-THIENYL)-1,2,5-THIADIAZOLIDIN-3-ONE 1,1-DIOXIDE	Tyrosine-protein phosphatase non-receptor type 1	Ki (nM)	16000	N/A	N/A	Details