High-throughput screening of the P&GP corporate repository against several protein tyrosine phosphatases identified the sulfamic acid moiety as potential phosphotyrosine mimetic. Incorporation of the sulfamic acid onto a 1,2,3,4-tetrahydroisoquinoline scaffold provided a promising starting point for PTP1B inhibitor design. 2006 Elsevier Ltd. All rights reserved. The PTPase PTP1B has been shown to be involved in the insulin signaling cascade as a negative regulator of insulin signaling. There is a growing body of evidence to suggest that inhibition of PTP1B can enhance insulin signaling primarily through prolonged activation of the insulin receptor. Recent studies have shown that PTP1B knock-out mice exhibit increased insulin sensitivity. In addition, treatment of animal models of type-2 diabetes with antisense oligonucleotides has been shown to normalize blood glucose levels. These results have spurred the research community to develop small molecule inhibitors of PTP1B for the treatment of type-2 diabetes and several groups have reported compounds to this end. 0960-894X/$ see front matter 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2005.12.051