|2nta, resolution 2.10Å ()|
|Gene:||PTPN1, PTP1B (Homo sapiens)|
|Related:||2nt7, 2hcx, 2hce, 2hfa|
Crystal Structure of PTP1B-inhibitor Complex
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.
Probing acid replacements of thiophene PTP1B inhibitors., 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, Bioorg Med Chem Lett. 2007 May 15;17(10):2913-20. Epub 2007 Feb 20. PMID:17336064
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
About this Structure
- 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. PMID:17336064 doi:10.1016/j.bmcl.2007.02.043