α-Naphthylaminopropan-2-ol Derivatives as BACE1 Inhibitors
Valentina Asso Dr.
Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, I-56126 Pisa (Italy), Fax: (+39) 050 2219553
Search for more papers by this authorElisa Ghilardi Dr.
Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, I-56126 Pisa (Italy), Fax: (+39) 050 2219553
Search for more papers by this authorSimone Bertini Dr.
Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, I-56126 Pisa (Italy), Fax: (+39) 050 2219553
Search for more papers by this authorMaria Digiacomo Dr.
Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, I-56126 Pisa (Italy), Fax: (+39) 050 2219553
Search for more papers by this authorCarlotta Granchi
Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, I-56126 Pisa (Italy), Fax: (+39) 050 2219553
Search for more papers by this authorFilippo Minutolo Prof. Dr.
Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, I-56126 Pisa (Italy), Fax: (+39) 050 2219553
Search for more papers by this authorSimona Rapposelli Dr.
Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, I-56126 Pisa (Italy), Fax: (+39) 050 2219553
Search for more papers by this authorAndrea Bortolato Dr.
Molecular Modeling Section, Dipartimento di Scienze Farmaceutiche, Università di Padova, Via Marzolo 5, I-35131 Padova (Italy)
Search for more papers by this authorStefano Moro Prof. Dr.
Molecular Modeling Section, Dipartimento di Scienze Farmaceutiche, Università di Padova, Via Marzolo 5, I-35131 Padova (Italy)
Search for more papers by this authorMarco Macchia Prof. Dr.
Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, I-56126 Pisa (Italy), Fax: (+39) 050 2219553
Search for more papers by this authorValentina Asso Dr.
Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, I-56126 Pisa (Italy), Fax: (+39) 050 2219553
Search for more papers by this authorElisa Ghilardi Dr.
Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, I-56126 Pisa (Italy), Fax: (+39) 050 2219553
Search for more papers by this authorSimone Bertini Dr.
Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, I-56126 Pisa (Italy), Fax: (+39) 050 2219553
Search for more papers by this authorMaria Digiacomo Dr.
Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, I-56126 Pisa (Italy), Fax: (+39) 050 2219553
Search for more papers by this authorCarlotta Granchi
Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, I-56126 Pisa (Italy), Fax: (+39) 050 2219553
Search for more papers by this authorFilippo Minutolo Prof. Dr.
Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, I-56126 Pisa (Italy), Fax: (+39) 050 2219553
Search for more papers by this authorSimona Rapposelli Dr.
Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, I-56126 Pisa (Italy), Fax: (+39) 050 2219553
Search for more papers by this authorAndrea Bortolato Dr.
Molecular Modeling Section, Dipartimento di Scienze Farmaceutiche, Università di Padova, Via Marzolo 5, I-35131 Padova (Italy)
Search for more papers by this authorStefano Moro Prof. Dr.
Molecular Modeling Section, Dipartimento di Scienze Farmaceutiche, Università di Padova, Via Marzolo 5, I-35131 Padova (Italy)
Search for more papers by this authorMarco Macchia Prof. Dr.
Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, I-56126 Pisa (Italy), Fax: (+39) 050 2219553
Search for more papers by this authorGraphical Abstract
Fast and healthy (molecular) weight loss! A relatively large BACE1 inhibitor containing a hydroxyethylamine aspartyl protease inhibitor motif was identified by high-throughput screening, and has inspired the design of new “lighter”, biologically active derivatives, representing a promising new class anti-Alzheimer's drugs.
References
- 1G. G. Glenner, C. W. Wong, Biochem. Biophys. Res. Commun. 1984, 120, 885–890.
- 2C. Ballatore, V. M. Y. Lee, J. Q. Trojanowski, Nat. Rev. Neurosci. 2007, 8, 663–672.
- 3M. S. Forman, J. Q. Trojanowski, V. M. Y. Lee, Nat. Med. 2004, 10, 1055–1063.
- 4V. John, J. P. Beck, M. J. Bienkowski, S. Sinha, R. L. Heinrikson, J. Med. Chem. 2003, 46, 4625–4630.
- 5
- 5aJ. C. Barrow, K. E. Rittle, P. L. Ngo, H. G. Selnick, S. L. Graham, S. M. Pitzenberger, G. B. McGaughey, D. Colussi, M. T. Lai, Q. Huang, K. Tugusheva, A. S. Espeseth, A. J. Simon, S. K. Munshi, J. P. Vacca, ChemMedChem 2007, 2, 995–999;
- 5bM. C. Maillard, R. K. Hom, T. E. Benson, J. B. Moon, S. Mamo, M. Bienkowski, A. G. Tomasselli, D. D. Woods, D. B. Prince, D. J. Paddock, T. L. Emmons, J. A. Tucker, M. S. Dappen, L. Brogley, E. D. Thorsett, N. Jewett, S. Sinha, V. John, J. Med. Chem. 2007, 50, 776–781.
- 6V. Porcari, L. Magnoni, G. C. Terstappen, W. Fecke, Assay Drug Dev. Technol. 2005, 3, 287–297.
- 7G. F. Ecker, C. R. Noe, Curr. Med. Chem. 2004, 11, 1617–1628.
- 8QikProp, version 3.0, Schrödinger, LLC, New York, NY, 2007.
- 9T. Ollevier, G. Lavie-Compin, Tetrahedron Lett. 2002, 43, 7891–7893.
- 10S. Patel, L. Vuillard, A. Cleasby, C. W. Murray, J. Yon, J. Mol. Biol. 2004, 343, 407–416.
- 11V. Limongelli, L. Marinelli, S. Cosconati, H. A. Braun, B. Schmidt, E. Novellino, ChemMedChem 2007, 2, 667–678.
- 12Schrödinger Suite 2007 Induced Fit Docking protocol; Glide version 4.5, Schrödinger, LLC, New York, NY, 2005; Prime version 1.6, Schrödinger, LLC, New York, NY, 2005.
- 13W. Sherman, T. Day, M. P. Jacobson, R. A. Friesner, R. Farid, J. Med. Chem. 2006, 49, 534–555.
- 14 The deshydroxy analogues of compounds 1 and 2 b were highly insoluble under the BACE1 inhibition assay conditions and so their activities could not be verified.
- 15T. Fujimoto, Y. Matsushita, H. Gouda, N. Yamaotsu, S. Hirono, Bioorg. Med. Chem. Lett. 2008, 18, 2771–2775.
- 16H. M. Berman, J. Westbrook, Z. Feng, G. Gilliland, T. N. Bhat, H. Weissig, I. N. Shindyalov, P. E. Bourne, Nucleic Acids Res. 2000, 28, 235–242.
- 17M. J. Hartshorn, M. L. Verdonk, G. Chessari, S. C. Brewerton, W. T. M. Mooij, P. N. Mortenson, C. W. Murray, J. Med. Chem. 2007, 50, 726–741.
- 18M. Stahl, Perspectives, Drug Discovery Des. 2000, 20, 83–98.
- 19MOE (The Molecular Operating Environment) Version 2006.08, software available from Chemical Computing Group Inc., 1010 Sherbrooke Street West, Suite 910, Montreal, Canada H3A 2R7. http://www.chemcomp.com.
- 20Glide, version 4.5, Schrödinger, LLC, New York, NY, 2007.
- 21W. D. C. Cornell, P. Cieplak, C. I. Bayly, I. R. Gould, K. M. Merz, D. M. Ferguson, D. C. Spellmeyer, T. Fox, J. W. Caldwell, P. A. Kollman, J. Am. Chem. Soc. 1995, 117, 5179–5196.
- 22T. Halgren, J. Comput. Chem. 1996, 17, 490–519.
- 23A. Jakalian, D. B. Jack, C. I. Bayly, J. Comput. Chem. 2002, 23, 1623–1641.
- 24Maestro, version 8.0, Schrödinger, LLC, New York, NY, 2007.
- 25LigPrep, version 2.1, Schrödinger, LLC, New York, NY, 2005.