Structure-based design of highly selective β-secretase inhibitors: Synthesis, biological evaluation, and protein-ligand x-ray crystal structure

Journal of Medicinal Chemistry

Volumn 55, Issue 21, 2012, Pages 9195-9207

  Ghosh, Arun K ^a   Venkateswara Rao, Kalapala ^a   Yadav, Navnath D ^a   Anderson, David D ^a   Gavande, Navnath ^a   Huang, Xiangping ^b   Terzyan, Simon ^b   Tang, Jordan ^b  

^a PURDUE UNIVERSITY   (United States)

^b UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BETA SECRETASE; BETA SECRETASE INHIBITOR;

ARTICLE; CRYSTAL STRUCTURE; DRUG DESIGN; DRUG POTENCY; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; HUMAN; REACTION ANALYSIS; STRUCTURE ANALYSIS;

AMIDES; AMYLOID PRECURSOR PROTEIN SECRETASES; CELL LINE, TUMOR; CELL MEMBRANE PERMEABILITY; CRYSTALLOGRAPHY, X-RAY; DRUG DESIGN; HUMANS; INDOLES; LIGANDS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PHTHALIC ACIDS; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONAMIDES;

EID: 84868518625     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm3008823     Document Type: Article

References (31)

1. Goedert, M.; Spillantini, M. G. A Century of Alzheimer's Disease Science 2006, 314, 777-781
2. Selkoe, D. J.; Schenk, D. Alzheimer's Disease: Molecular Understanding Predicts Amyloid-Based Therapeutics Annu. Rev. Pharmacol. Toxicol. 2003, 43, 545-584
3. Citron, M. Alzheimer's Disease: Strategies for Disease Modification Nat. Rev. Drug Discovery 2010, 9, 387-398
4. Billings, L. M.; Oddo, S.; Green, K. N.; McGaugh, J. L.; LaFerla, F. M. Intraneuronal Aβ Causes the Onset of Early Alzheimer's Disease-Related Cognitive Deficits in Transgenic Mice Neuron 2005, 45, 675-688
5. Ghosh, A. K.; Brindisi, M.; Tang, J. Developing β-Secretase Inhibitors for Treatment of Alzheimer's Disease J. Neurochem. 2012, 120, 71-83
6. Tang, J.; Hong, L.; Ghosh, A. K. The Discovery of β-Secretase and Development Toward a Clinical Inhibitor for AD: An Exciting Academic Collaboration. In Aspartic Acid Proteases as Therapeutic Targets; Ghosh, A. K., Ed.; Wiley-VCH: Weinheim, 2010; Vol. 45, pp 413-440.
7. Ghosh, A. K.; Shin, D.; Downs, D.; Koelsch, G.; Lin, X.; Ermolieff, J.; Tang, J. Design of Potent Inhibitors for Human Brain Memapsin 2 (β-Secretase) J. Am. Chem. Soc. 2000, 122, 3522-3523
8. Hong, L.; Koelsch, G.; Lin, X.; Wu, S.; Terzyan, S.; Ghosh, A. K.; Zhang, X. C.; Tang, J. Structure of the Protease Domain of Memapsin 2 (β-Secretase) Complexed with Inhibitor Science 2000, 290, 150-153
9. Ghosh, A. K.; Kumaragurubaran, N.; Hong, L.; Kulkarni, S.; Xu, X.; Miller, H. B.; Reddy, D. S.; Weerasena, V.; Turner, R.; Chang, W.; Koelsch, G.; Tang, J. Potent Memapsin 2 (β-Secretase) Inhibitors: Design, Synthesis, Protein-Ligand X-ray Structure, and in vivo Evaluation Bioorg. Med. Chem. Lett. 2008, 18, 1031-1036
10. Chang, W.; Huang, X.; Downs, D.; Cirrito, J. R.; Koelsch, G.; Holtzman, D. M.; Ghosh, A. K.; Tang, J. β-Secretase Inhibitor GRL-8234 Rescues Age-related Cognitive Decline in APP Transgenic Mice FASEB J. 2011, 25, 775-784
11. Turner, R. T.; Loy, J. A.; Nguyen, C.; Devasamudram, T.; Ghosh, A. K.; Koelsch, G.; Tang, J. Specificity of Memapsin 1 and Its Implications on the Design of Memapsin 2 (β-Secretase) Inhibitor Selectivity Biochemistry 2002, 41, 8742-8746
12. Diment, S.; Leech, M. S.; Stahl, P. D. Cathepsin D is Membrane-Associated in Macrophage Endosomes J. Biol. Chem. 1988, 263, 6901-6907
13. Koike, M.; Nakanishi, H.; Saftig, P.; Ezaki, J.; Isahara, K.; Ohsawa, Y.; Schulz-Schaeffer, W.; Watanabe, T.; Waguri, S.; Kametaka, S.; Shibata, M.; Yamamoto, K.; Kominami, E.; Peters, C.; Figura, K.; Uchiyama, Y. Cathepsin D Deficiency Induces Lysosomal Storage with Ceroid Lipofuscin in Mouse CNS Neurons J. Neurosci. 2000, 20, 6898-6906
14. Saftig, P.; Hetman, M.; Schmahl, W.; Weber, K.; Heine, L.; Mossmann, H.; Koster, A.; Hess, B.; Evers, M.; von Figura, K. EMBO J. 1995, 14, 3599-3608
15. Ghosh, A. K.; Kumaragurubaran, N.; Hong, L.; Lei, H.; Hussain, K. A.; Liu, C.-F.; Devasamudram, T.; Weerasena, V.; Turner, R.; Koelsch, G.; Bilcer, G.; Tang, J. Design, Synthesis and X-ray Structure of Protein-Ligand Complexes: Important Insight into Selectivity of Memapsin 2 (β-Secretase) Inhibitors J. Am. Chem. Soc. 2006, 128, 5310-5311
16. Labby, K. J.; Xue, F.; Kraus, J. M.; Ji, H.; Mataka, J.; Li, H.; Martásek, P.; Roman, L. J.; Poulos, T. L.; Silverman, R. B. Intramolecular Hydrogen Bonding: A Potential Strategy for More Bioavailable Inhibitors of Neuronal Nitric Oxide Synthase Bioorg. Med. Chem. 2012, 20, 2435-2443
17. Kuhn, B.; Mohr, P.; Stahl, M. Intramolecular Hydrogen Bonding in Medicinal Chemistry J. Med. Chem. 2010, 53, 2601-2611
18. Iserloh, U.; Cumming, J. N. Peptidomimetic BACE1 Inhibitors for Treatment of Alzheimer's Disease: Design and Evolution. In Aspartic Acid Proteases as Therapeutic Targets; Ghosh, A. K., Ed.; Wiley-VCH: Weinheim, 2010; Vol. 45, pp 441-479.
19. 2NH] Reduced Amide Isosteres Bioorg. Med. Chem. Lett. 2006, 16, 3635-3638
20. Velmourougane, G.; Harbut, M. B.; Dalal, S.; McGowan, S.; Oellig, C. A.; Meinhardt, N.; Whisstock, J. C.; Klemba, M.; Greenbaum, D. C. Synthesis of New (-)-Bestatin-Based Inhibitor Libraries Reveals a Novel Binding Mode in the S1 Pocket of the Essential Malaria M1Metalloaminopeptidase J. Med. Chem. 2011, 54, 1655-1666
21. Ghosh, A. K.; Kumaragurubaran, N.; Hong, L.; Kulkarni, S. S.; Xu, X.; Chang, W.; Weerasena, V.; Turner, R.; Koelsch, G.; Bilcer, G.; Tang, J. Design, Synthesis, and X-ray Structure of Potent Memapsin 2 (β-Secretase) Inhibitors with Isophthalamide Derivatives as the P2-P3-Ligands J. Med. Chem. 2007, 50, 2399-2407
22. Andurkar, S. V.; Stables, J. P.; Kohn, H. Synthesis and Anticonvulsant Activities of (R)-(O)-Methylserine Derivatives Tetrahedron: Asymmetry 1998, 9, 3841-3854
23. Charrier, N.; Clarke, B.; Cutler, L.; Demont, E.; Dingwall, C.; Dunsdon, R.; East, P.; Hawkins, J.; Howes, C.; Hussain, I.; Jeffrey, P.; Maile, G.; Matico, R.; Mosley, J.; Naylor, A.; O'Brien, A.; Redshaw, S.; Rowland, P.; Soleil, V.; Smith, K. J.; Sweitzer, S.; Theobald, P.; Vesey, D.; Walter, D. S.; Wayne, G. Second Generation of Hydroxyethylamine BACE-1 Inhibitors: Optimizing Potency and Oral Bioavailability J. Med. Chem. 2008, 51, 3313-3317
24. Hubert, D. E.; Sally, R.; Simon, W. D. Tricyclic Indole Derivatives and Their Use in the Treatment of Alzheimer's Disease. WO 2004/094430 A1.
25. Charrier, N.; Demont, E.; Dunsdon, R; Maile, G.; Naylor, A.; OBrien, A.; Redshaw, S.; Theobald, P.; Vesey, D.; Walter, D. Synthesis of Indoles: Efficient Functionalisation of the 7-Position Synthesis 2006, 3467-3477
26. Fleming, P. R.; Sharpless, K. B. Selective Transformations of Threo-2,3-dihydroxy Esters J. Org. Chem. 1991, 56, 2869-2875
27. Memapsin 2 inhibition was measured using recombinant enzyme produced from E. coli expression. A fluorogenic substrate Arg-Glu(EDANS)-Glu-Val-Asn-Leu-Asp- Ala-Glu-Phe-Lys (Dabcyl)-Arg was used with a 0.47 μM concentration of the enzyme in 0.1 M Na-acetate + 5% dimethylsulfoxide, pH 4.5, at 37 °C. The excitation wavelength was 350 nm, and the emission wavelength was 490 nm. For details, please see Ermolieff, J.; Loy, J. A.; Koelsch, G.; Tang, J. Proteolytic Activation of Recombinant Pro-memapsin 2 (Pro-β-secretase) Studied with New Fluorogenic Substrates Biochemistry 2000, 39, 12450-12456
28. Chang, W. P.; Koelsch, G.; Wong, S.; Downs, D.; Da, H.; Weerasena, V.; Gordon, B.; Devasamudram, T.; Bilcer, G.; Ghosh, A. K.; Tang, J. In vivo Inhibition of Aβ Production by Memapsin 2 (β-Secretase) Inhibitors J. Neurochem. 2004, 89, 1409-1416
29. Patel, S.; Vuillard, L.; Cleasby, A.; Murray, C. W.; Yon, J. Apo and Inhibitor Complex Structures of BACE (β-Secretase) J. Mol. Biol. 2004, 343, 407-416
30. Charrier, N.; Clarke, B.; Cutler, L.; Demont, E.; Dingwall, C.; Dunsdon, R.; Hawkins, J.; Howes, C.; Hubbard, J.; Hussain, I.; Maile, G.; Matico, R.; Mosley, J.; Naylor, A.; O'Brien, A.; Redshaw, S.; Rowland, P.; Soleil, V.; Smith, K. J.; Sweitzer, S.; Theobald, P.; Vesey, D.; Walter, D. S.; Wayne, G. Second Generation of BACE-1 Inhibitors Part 3: Towards Non-hydroxyethylamine Transition State Mimetics Bioorg. Med. Chem. Lett. 2009, 19, 3674-3678
31. Berman, H. M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T. N.; Weissig, H.; Shindyalov, I. N.; Bourne, P. E. The Protein Data Bank Nucleic Acids Res. 2000, 28, 235-242