title: Synthesis of benzopentathiepin analogs and their evaluation as inhibitors of the phosphatase STEP.
abstract: Striatal-enriched protein tyrosine phosphatase (STEP) is a brain specific protein tyrosine phosphatase that has been implicated in many neurodegenerative diseases, such as Alzheimer's disease. We recently reported the benzopentathiepin TC-2153 as a potent inhibitor of STEP in vitro, cells and animals. Herein, we report the synthesis and evaluation of TC-2153 analogs in order to define what structural features are important for inhibition and to identify positions tolerant of substitution for further study. The trifluoromethyl substitution is beneficial for inhibitor potency, and the amine is tolerant of acylation, and thus provides a convenient handle for introducing additional functionality such as reporter groups.
authors: Department of Chemistry, Yale University, New Haven, CT 06520, United States.
authors: Tyler D
authors: TD
authors: Baguley
authors: Department of Psychiatry, Yale University, New Haven, CT 06520, United States.
authors: Angus C
authors: AC
authors: Nairn
authors: Department of Psychiatry, Yale University, New Haven, CT 06520, United States; Department of Neurobiology, Yale University, New Haven, CT 06520, United States; Child Study Center, Yale University, New Haven, CT 06520, United States.
authors: Paul J
authors: PJ
authors: Lombroso
authors: Department of Chemistry, Yale University, New Haven, CT 06520, United States. Electronic address: jonathan.ellman@yale.edu.
authors: Jonathan A
authors: JA
authors: Ellman
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology; D000818:Animals; D001582:Benzothiepins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D054879:Halogenation; D008745:Methylation; D051379:Mice; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats
chemical_list: C559038:8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine; D001582:Benzothiepins; D004791:Enzyme Inhibitors; D017027:Protein Tyrosine Phosphatases
keywords: Alzheimer’s disease; Inhibitor; Phosphatase; Redox; STEP