STRUCTURE-BASED DESIGN AND SYNTHESIS OF SMALL-MOLECULE PROTEIN-TYROSINE-PHOSPHATASE 1B INHIBITORS

Protein-tyrosine phosphatase (PTP) inhibitors are attractive as potent ial signal transduction-directed therapeutics which may be useful in t he treatment of a variety of diseases. We have previously reported the X-ray structure of 1,1-difluoro-1-(2-naphthalenyl)methyl] phosphonic acid (4) complexed with the human the protein-tyrosine phosphatase 1B (PTP1B) and its use in the design of an analogue which binds with high er affinity within the catalytic site (Burke, T. R., Jr. et al. Bioche mistry 1996, 35, 15989). In the current study, new naphthyldifluoromet hyl phosphonic acids were designed bearing acidic functionality intend ed to interact with the PTP1B Arg47, which is situated just outside th e catalytic pocket. This residue has been shown previously to provide key interactions with acidic residues of phosphotyrosyl-containing pep tide substrates. Consistent with trends predicted by molecular dynamic s calculations, the new analogues bound with 7- to 14-fold higher affi nity than the parent 4, in principal validating the design rationale. (C) 1998 Elsevier Science Ltd. All rights reserved.