Sparks Richard B, Polam Padmaja, Zhu Wenyu, Crawley Matthew L, Takvorian Amy, McLaughlin Erin, Wei Min, Ala Paul J, Gonneville Lucie, Taylor Nancy, Li Yanlong, Wynn Richard, Burn Timothy C, Liu Phillip C C, Combs Andrew P
Incyte Corporation, Discovery Chemistry, Experimental Station, Route 141 and Henry Clay Road, Wilmington, DE 19880, USA.
Bioorg Med Chem Lett. 2007 Feb 1;17(3):736-40. doi: 10.1016/j.bmcl.2006.10.079. Epub 2006 Oct 28.
Benzothiazole benzimidazole (S)-isothiazolidinone ((S)-IZD) derivatives 5 were discovered through a peptidomimetic modification of the tripeptide (S)-IZD protein tyrosine phosphatase 1B (PTP1B) inhibitor 1. These derivatives are potent, competitive, and reversible inhibitors of PTP1B with improved caco-2 permeability. An X-ray co-crystal structure of inhibitor 5/PTP1B at 2.2A resolution demonstrated that the benzothiazole benzimidazole forms bi-dentate H-bonds to Asp48, and the benzothiazole interacts with the surface of the protein in a solvent exposed region towards the C-site. The design, synthesis, and SAR of this novel series of benzothiazole benzimidazole containing (S)-IZD inhibitors of PTP1B are presented herein.
通过对三肽（S）-异噻唑烷酮蛋白酪氨酸磷酸酶1B（PTP1B）抑制剂1进行拟肽修饰，发现了苯并噻唑苯并咪唑（S）-异噻唑烷酮（（S）-IZD）衍生物5。这些衍生物是PTP1B的强效、竞争性和可逆抑制剂，其caco-2通透性有所提高。抑制剂5与PTP1B在2.2埃分辨率下的X射线共晶体结构表明，苯并噻唑苯并咪唑与Asp48形成双齿氢键，且苯并噻唑在朝向C位点的溶剂暴露区域与蛋白质表面相互作用。本文介绍了这一系列含苯并噻唑苯并咪唑的新型PTP1B（S）-IZD抑制剂的设计、合成及构效关系。
