Discovery and optimization of a novel spiropyrrolidine inhibitor of β-secretase (BACE1) through fragment-based drug design

Journal of Medicinal Chemistry

Volumn 55, Issue 21, 2012, Pages 9069-9088

  Efremov, Ivan V ^a   Vajdos, Felix F ^a   Borzilleri, Kris A ^a   Capetta, Steven ^a   Chen, Hou ^a   Dorff, Peter H ^a   Dutra, Jason K ^a   Goldstein, Steven W ^a   Mansour, Mahmoud ^a   McColl, Alexander ^a   Noell, Stephen ^a   Oborski, Christine E ^a   Oconnell, Thomas N ^a   Osullivan, Theresa J ^a   Pandit, Jayvardhan ^a   Wang, Hong ^a   Wei, Binqing ^a   Withka, Jane M ^a  

^a PFIZER INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMYLOID BETA PROTEIN; BETA SECRETASE 1; BETA SECRETASE INHIBITOR; MULTIDRUG RESISTANCE PROTEIN; PYRROLIDINE DERIVATIVE; SPIRO COMPOUND;

ANIMAL TISSUE; ARTICLE; CONTROLLED STUDY; DRUG DESIGN; DRUG PENETRATION; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; NONHUMAN; NUCLEAR MAGNETIC RESONANCE; PHYSICAL CHEMISTRY; PROTEIN DEGRADATION; X RAY CRYSTALLOGRAPHY;

AMYLOID PRECURSOR PROTEIN SECRETASES; ASPARTIC ACID ENDOPEPTIDASES; CRYSTALLOGRAPHY, X-RAY; DRUG DESIGN; HUMANS; INDOLES; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PYRROLIDINES; SPIRO COMPOUNDS; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84868526878     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm201715d     Document Type: Article

References (54)

1. Tiraboschi, P.; Hansen, L. A.; Thal, L. J.; Corey-Bloom, J. The importance of neuritic plaques and tangles to the development and evolution of AD Neurology 2004, 62 (11) 1984-1989
2. Hardy, J.; Allsop, D. Amyloid deposition as the central event in the aetiology of Alzheimers disease Trends Pharmacol. Sci. 1991, 12, 383-388
3. Bredesen, D. E.; Koo, E.H., BACE, APP Processing, and Signal Transduction in Alzheimers Disease. In BACE: Lead Target for Orchestrated Therapy of Alzheimers Disease; John, V., Ed.; John Wiley & Sons: Hoboken, NJ, 2010; pp 1-13.
4. 2008 Alzheimers disease facts and figures. Alzheimers Dementia 2008, 4 (2), 110-133.
5. Wolfe, M. S. The gamma;-Secretase Complex: Membrane-Embedded Proteolytic Ensemble Biochemistry 2006, 45 (26) 7931-7939
6. Eder, J.; Hommel, U.; Cumin, F.; Martoglio, B.; Gerhartz, B. Aspartic Proteases in Drug Discovery Curr. Pharm. Des. 2007, 13, 271-285
7. Tang, J.; James, M. N. G.; Hsu, I. N.; Jenkins, J. A.; Blundell, T. L. Structural evidence for gene duplication in the evolution of the acid proteases Nature 1978, 271 (5646) 618-621
8. Coates, L.; Erskine, P. T.; Mall, S.; Gill, R.; Wood, S. P.; Myles, D. A. A.; Cooper, J. B. X-ray, neutron and NMR studies of the catalytic mechanism of aspartic proteinases Eur. Biophys. J. 2006, 35, 559-566
9. Tomasselli, A. G.; Bienkowski, M. BACE Biological Assays. In BACE: Lead Target for Orchestrated Therapy of Alzheimers Disease; John, V., Ed.; John Wiley and Sons: New York, 2009.
10. Abramowitz, N.; Schechter, I.; Berger, A. On the size of the active site in proteases II. Carboxypeptidase-A Biochem. Biophys. Res. Commun. 1967, 29 (6) 862-867
11. 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 (5489) 150-153
12. Schechter, I.; Berger, A. On the size of the active site in proteinases. I. Papain Biochem. Biophys. Res. Commun. 1967, 27, 157-162
13. Schechter, I.; Berger, A. On the active site of proteases. III. Mapping the active site of papain; specific peptide inhibitors of papain Biochem. Biophys. Res. Commun. 1968, 32 (5) 898-902
14. Turner, R. T.; Hong, L.; Koelsch, G.; Ghosh, A. K.; Tang, J. Structural Locations and Functional Roles of New Subsites S5, S6, and S7 in Memapsin 2 (β-Secretase) Biochemistry 2005, 44 (1) 105-112
15. Congreve, M.; Aharony, D.; Albert, J.; Callaghan, O.; Campbell, J.; Carr, R. A. E.; Chessari, G.; Cowan, S.; Edwards, P. D.; Frederickson, M.; McMenamin, R.; Murray, C. W.; Patel, S.; Wallis, N. Application of Fragment Screening by X-ray Crystallography to the Discovery of Aminopyridines as Inhibitors of β-Secretase J. Med. Chem. 2007, 50 (6) 1124-1132
16. Edwards, P. D.; Albert, J. S.; Sylvester, M.; Aharony, D.; Andisik, D.; Callaghan, O.; Campbell, J. B.; Carr, R. A.; Chessari, G.; Congreve, M.; Frederickson, M.; Folmer, R. H. A.; Geschwindner, S.; Koether, G.; Kolmodin, K.; Krumrine, J.; Mauger, R. C.; Murray, C. W.; Olsson, L.-L.; Patel, S.; Spear, N.; Tian, G. Application of Fragment-Based Lead Generation to the Discovery of Novel, Cyclic Amidine β-Secretase Inhibitors with Nanomolar Potency, Cellular Activity, and High Ligand Efficiency J. Med. Chem. 2007, 50 (24) 5912-5925
17. Geschwindner, S.; Olsson, L.-L.; Albert, J. S.; Deinum, J.; Edwards, P. D.; de Beer, T.; Folmer, R. H. A. Discovery of a Novel Warhead against β-Secretase through Fragment-Based Lead Generation J. Med. Chem. 2007, 50 (24) 5903-5911
18. Kuglstatter, A.; Stahl, M.; Peters, J.-U.; Huber, W.; Stihle, M.; Schlatter, D.; Benz, J.; Ruf, A.; Roth, D.; Enderle, T.; Hennig, M. Tyramine fragment binding to BACE-1 Bioorg. Med. Chem. Lett. 2008, 18 (4) 1304-1307
19. Murray, C. W.; Callaghan, O.; Chessari, G.; Cleasby, A.; Congreve, M.; Frederickson, M.; Hartshorn, M. J.; McMenamin, R.; Patel, S.; Wallis, N. Application of Fragment Screening by X-ray Crystallography to β-Secretase J. Med. Chem. 2007, 50 (6) 1116-1123
20. Chessari, G.; Woodhead, A. J. From fragment to clinical candidate-a historical perspective Drug Discovery Today 2009, 14 (13-14) 668-675
21. Hamada, Y.; Kiso, Y. Recent progress in the drug discovery of non-peptidic BACE1 inhibitors Expert Opin. Drug Discovery 2009, 4 (4) 391-416
22. Feng, B.; Mills, J. B.; Davidson, R. E.; Mireles, R. J.; Janiszewski, J. S.; Troutman, M. D.; de Morais, S. M. In Vitro P-glycoprotein Assays to Predict the in Vivo Interactions of P-glycoprotein with Drugs in the Central Nervous System Drug Metab. Dispos. 2008, 36 (2) 268-275
23. Coburn, C. A.; Stachel, S. J.; Li, Y.-M.; Rush, D. M.; Steele, T. G.; Chen-Dodson, E.; Holloway, M. K.; Xu, M.; Huang, Q.; Lai, M.-T.; DiMuzio, J.; Crouthamel, M.-C.; Shi, X.-P.; Sardana, V.; Chen, Z.; Munshi, S.; Kuo, L.; Makara, G. M.; Annis, D. A.; Tadikonda, P. K.; Nash, H. M.; Vacca, J. P.; Wang, T. Identification of a Small Molecule Nonpeptide Active Site β-Secretase Inhibitor That Displays a Nontraditional Binding Mode for Aspartyl Proteases J. Med. Chem. 2004, 47 (25) 6117-6119
24. Cole, D. C.; Manas, E. S.; Stock, J. R.; Condon, J. S.; Jennings, L. D.; Aulabaugh, A.; Chopra, R.; Cowling, R.; Ellingboe, J. W.; Fan, K. Y.; Harrison, B. L.; Hu, Y.; Jacobsen, S.; Jin, G.; Lin, L.; Lovering, F. E.; Malamas, M. S.; Stahl, M. L.; Strand, J.; Sukhdeo, M. N.; Svenson, K.; Turner, M. J.; Wagner, E.; Wu, J.; Zhou; Bard, J. Acylguanidines as Small-Molecule β-Secretase Inhibitors J. Med. Chem., 2006, 49 (21) 6158-6161
25. Cole, D. C.; Stock, J. R.; Chopra, R.; Cowling, R.; Ellingboe, J. W.; Fan, K. Y.; Harrison, B. L.; Hu, Y.; Jacobsen, S.; Jennings, L. D.; Jin, G.; Lohse, P. A.; Malamas, M. S.; Manas, E. S.; Moore, W. J.; ODonnell, M.-M.; Olland, A. M.; Robichaud, A. J.; Svenson, K.; Wu, J.; Wagner, E.; Bard, J. Acylguanidine inhibitors of β-secretase: optimization of the pyrrole ring substituents extending into the S1 and S3 substrate binding pockets Bioorg. Med. Chem. Lett. 2008, 18 (3) 1063-1066
26. Fobare, W. F.; Solvibile, W. R.; Robichaud, A. J.; Malamas, M. S.; Manas, E.; Turner, J.; Hu, Y.; Wagner, E.; Chopra, R.; Cowling, R.; Jin, G.; Bard, J. Thiophene substituted acylguanidines as BACE1 inhibitors Bioorg. Med. Chem. Lett. 2007, 17 (19) 5353-5356
27. Baxter, E. W.; Conway, K. A.; Kennis, L.; Bischoff, F.; Mercken, M. H.; De Winter, H. L.; Reynolds, C. H.; Tounge, B. A.; Luo, C.; Scott, M. K.; Huang, Y.; Braeken, M.; Pieters, S. M. A.; Berthelot, D. J. C.; Masure, S.; Bruinzeel, W. D.; Jordan, A. D.; Parker, M. H.; Boyd, R. E.; Qu, J.; Alexander, R. S.; Brenneman, D. E.; Reitz, A. B. 2-Amino-3,4-dihydroquinazolines as Inhibitors of BACE-1 (β-Site APP Cleaving Enzyme): Use of Structure Based Design to Convert a Micromolar Hit into a Nanomolar Lead J. Med. Chem. 2007, 50 (18) 4261-4264
28. Pajouhesh, H.; Lenz, G. R. Medicinal Chemical Properties of Successful Central Nervous System Drugs NeuroRX 2005, 2 (4) 541-553
29. Wager, T. T.; Chandrasekaran, R. Y.; Hou, X.; Troutman, M. D.; Verhoest, P. R.; Villalobos, A.; Will, Y. Defining Desirable Central Nervous System Drug Space through the Alignment of Molecular Properties, in Vitro ADME, and Safety Attributes ACS Chem. Neurosci. 2010, 1 (6) 420-434
30. Lau, W. F.; Withka, J. M.; Hepworth, D.; Magee, T. V.; Du, J.; Bakken, G. A.; Miller, M. D.; Hendsch, Z. S.; Thanabal, V.; Kolodziej, S. A.; Xing, L.; Hu, Q.; Narasimhan, L. S.; Love, R.; Charlton, M. E.; Hughes, S.; Van Hoorn, W. P.; Mills, J. E. Design of a Multi-purpose Fragment Screening Library using Molecular Complexity and Orthogonal Diversity Metrics J. Comput.-Aided Mol. Des. 2011, 1-16
31. Tomasselli, A. G.; Paddock, D. J.; Emmons, T. L.; Mildner, A. M.; Leone, J. W.; Lull, J. M.; Cialdella, J. I.; Prince, D. B.; Fischer, H. D.; Heinrikson, R. L.; Benson, T. E. High Yield Expression of Human BACE Constructs in Escherichia coli for Refolding, Purification, and High Resolution Diffracting Crystal Forms Protein Pept. Lett. 2008, 15 (2) 131-143
32. Pflugrath, J. W. The finer things in X-ray diffraction data collection Acta Crystallogr., Sect. D: Biol. Crystallogr. 1999, 55, 1718-1725
33. Bricogne, G.; Blanc, E.; Brandl, M.; Flensburg, C.; Keller, P.; Paciorek, W.; Roversi, P.; Smart, O. S.; Vonrhein, C.;; Womack, T. O., BUSTER; Global Phasing Ltd.: Cambridge, UK, 2009.
34. Barrow, J. C.; Stauffer, S. R.; Rittle, K. E.; Ngo, P. L.; Yang, Z.; Selnick, H. G.; Graham, S. L.; Munshi, S.; McGaughey, G. B.; Holloway, M. K.; Simon, A. J.; Price, E. A.; Sankaranarayanan, S.; Colussi, D.; Tugusheva, K.; Lai, M.-T.; Espeseth, A. S.; Xu, M.; Huang, Q.; Wolfe, A.; Pietrak, B.; Zuck, P.; Levorse, D. A.; Hazuda, D.; Vacca, J. P. Discovery and X-ray Crystallographic Analysis of a Spiropiperidine Iminohydantoin Inhibitor of β-Secretase J. Med. Chem. 2008, 51 (20) 6259-6262
35. Freskos, J. N.; Fobian, Y. M.; Benson, T. E.; Bienkowski, M. J.; Brown, D. L.; Emmons, T. L.; Heintz, R.; Laborde, A.; McDonald, J. J.; Mischke, B. V.; Molyneaux, J. M.; Moon, J. B.; Mullins, P. B.; Bryan Prince, D.; Paddock, D. J.; Tomasselli, A. G.; Winterrowd, G. Design of potent inhibitors of human β-secretase. Part 1 Bioorg. Med. Chem. Lett. 2007, 17 (1) 73-77
36. Maillard, M. C.; Hom, R. K.; Benson, T. E.; Moon, J. B.; Mamo, S.; Bienkowski, M.; Tomasselli, A. G.; Woods, D. D.; Prince, D. B.; Paddock, D. J.; Emmons, T. L.; Tucker, J. A.; Dappen, M. S.; Brogley, L.; Thorsett, E. D.; Jewett, N.; Sinha, S.; John, V. Design, Synthesis, and Crystal Structure of Hydroxyethyl Secondary Amine-Based Peptidomimetic Inhibitors of Human β-Secretase J. Med. Chem. 2007, 50 (4) 776-781
37. Hopkins, A. L.; Groom, C. R.; Alex, A. Ligand efficiency: a useful metric for lead selection Drug Discovery Today 2004, 9 (10) 430-431
38. Wang, Y.-S.; Liu, D.; Wyss, D. F. Competition STD NMR for the detection of high-affinity ligands and NMR-based screening Magn. Reson. Chem. 2004, 42 (6) 485-489
39. Liu, D.; Wang, Y.-S.; Gesell, J. J.; Wilson, E.; Beyer, B. M.; Wyss, D. F. Letter to the Editor: Backbone Resonance Assignments of the 45.3 kDa Catalytic Domain of Human BACE1 J. Biomol. NMR 2004, 29 (3) 425-426
40. ONeill, B. T. B.; James, G.; Brodney, M. A.; Chenard, L. K.; Coffman, K. J.; Deng, B.; Dorff, P. H.; Efremov, I.; Kauffman, G. W.; Kleinman, E. F.; Lanyon, L. F.; Lin, W.; Liston, D.; Mansour, M.; Martin, B. A.; Martinez Alsina, L.; McColl, A. S.; Murray, J. C.; Oborski, C. E.; Sahagan, B. G.; Vajdos, F.; Wessel, M. D Pyrrolidine β-secretase inhibitors for treatment of Alzheimers disease. 239th ACS National Meeting, San Francisco, CA, March 21-25, 2010.
41. Congreve, M.; Aharony, D.; Albert, J.; Callaghan, O.; Campbell, J.; Carr, R. A. E.; Chessari, G.; Cowan, S.; Edwards, P. D.; Frederickson, M.; McMenamin, R.; Murray, C. W.; Patel, S.; Wallis, N. Application of Fragment Screening by X-ray Crystallography to the Discovery of Aminopyridines as Inhibitors of β -Secretase J. Med. Chem. 2007, 50 (6) 1124-1132
42. Sealy, J. M.; Truong, A. P.; Tso, L.; Probst, G. D.; Aquino, J.; Hom, R. K.; Jagodzinska, B. M.; Dressen, D.; Wone, D. W. G.; Brogley, L.; John, V.; Tung, J. S.; Pleiss, M. A.; Tucker, J. A.; Konradi, A. W.; Dappen, M. S.; Toth, G.; Pan, H.; Ruslim, L.; Miller, J.; Bova, M. P.; Sinha, S.; Quinn, K. P.; Sauer, J.-M. Design and synthesis of cell potent BACE-1 inhibitors: structure-activity relationship of P1′ substituents Bioorg. Med. Chem. Lett. 2009, 19 (22) 6386-6391
43. Truong, A. P.; Probst, G. D.; Aquino, J.; Fang, L.; Brogley, L.; Sealy, J. M.; Hom, R. K.; Tucker, J. A.; John, V.; Tung, J. S.; Pleiss, M. A.; Konradi, A. W.; Sham, H. L.; Dappen, M. S.; Tóth, G.; Yao, N.; Brecht, E.; Pan, H.; Artis, D. R.; Ruslim, L.; Bova, M. P.; Sinha, S.; Yednock, T. A.; Zmolek, W.; Quinn, K. P.; Sauer, J.-M. Improving the permeability of the hydroxyethylamine BACE-1 inhibitors: structure-activity relationship of P2′ substituents Bioorg. Med. Chem. Lett. 2010, 20 (16) 4789-4794
44. Wang, Y.-S.; Strickland, C.; Voigt, J. H.; Kennedy, M. E.; Beyer, B. M.; Senior, M. M.; Smith, E. M.; Nechuta, T. L.; Madison, V. S.; Czarniecki, M.; McKittrick, B. A.; Stamford, A. W.; Parker, E. M.; Hunter, J. C.; Greenlee, W. J.; Wyss, D. F. Application of Fragment-Based NMR Screening, X-ray Crystallography, Structure-Based Design, and Focused Chemical Library Design to Identify Novel μM Leads for the Development of nM BACE-1 (β-Site APP Cleaving Enzyme 1) Inhibitors J. Med. Chem. 2009, 53 (3) 942-950
45. Kuglstatter, A.; Hennig, M. Fragment-Based Approaches for Identification of BACE Inhibitors. In BACE: Lead Target for Orchestrated Therapy of Alzheimers Disease; John, V., Ed.; John Wiley & Sons, Inc: Hoboken, NJ, 2010; pp 107-121.
46. Blum, A.; Böttcher, J.; Heine, A.; Klebe, G.; Diederich, W. E. Structure-Guided Design of C 2-Symmetric HIV-1 Protease Inhibitors Based on a Pyrrolidine Scaffold J. Med. Chem. 2008, 51 (7) 2078-2087
47. Böttcher, J.; Blum, A.; Dörr, S.; Heine, A.; Diederich, W.; Klebe, G. Targeting the Open-Flap Conformation of HIV-1 Protease with Pyrrolidine-Based Inhibitors ChemMedChem 2008, 3 (9) 1337-1344
48. Specker, E.; Böttcher, J.; Brass, S.; Heine, A.; Lilie, H.; Schoop, A.; Müller, G.; Griebenow, N.; Klebe, G. Unexpected Novel Binding Mode of Pyrrolidine-Based Aspartyl Protease Inhibitors: Design, Synthesis and Crystal Structure in Complex with HIV Protease ChemMedChem 2006, 1 (1) 106-117
49. Specker, E.; Böttcher, J.; Lilie, H.; Heine, A.; Schoop, A.; Müller, G.; Griebenow, N.; Klebe, G. An Old Target Revisited: Two New Privileged Skeletons and an Unexpected Binding Mode For HIV-Protease Inhibitors Angew. Chem., Int. Ed. 2005, 44 (20) 3140-3144
50. Stachel, S. J.; Steele, T. G.; Petrocchi, A.; Haugabook, S. J.; McGaughey, G.; Katharine, M.; Holloway, T.; Allison, S.; Munshi, P.; Zuck, D.; Colussi, K.; Tugasheva, A.; Wolfe, S. L.; Graham; Vacca, J. P. Discovery of pyrrolidine-based β-secretase inhibitors: Lead advancement through conformational design for maintenance of ligand binding efficiency Bioorg. Med. Chem. Lett. 2012, 22 (1) 240-244
51. Emsley, P.; Cowtan, K. Coot: Model-Building Tools for Molecular Graphics Acta Crystallogr., Sect. D: Biol. Crystallogr. 2004, 60, 2126-2132
52. Lambert, J. B.; Mark, H. W.; Magyar, E. S. Inductive enhancement of aryl participation J. Am. Chem. Soc. 1977, 99 (9) 3059-3067
53. Grüninger-Leitch, F.; Schlatter, D.; Küng, E.; Nelböck, P.; Döbeli, H. Substrate and Inhibitor Profile of BACE (β-Secretase) and Comparison with Other Mammalian Aspartic Proteases J. Biol. Chem. 2002, 277, 4687-4693
54. May, P. C.; Dean, R. A.; Lowe, S. L.; Martenyi, F.; Sheehan, S. M.; Boggs, L. N.; Monk, S. A.; Mathes, B. M.; Mergott, D. J.; Watson, B. M.; Stout, S. L.; Timm, D. E.; LaBell, E. S.; Gonzales, C. R.; Nakano, M.; Jhee, S. S.; Yen, M.; Ereshefsky, L.; Lindstrom, T. D.; Calligaro, D. O.; Cocke, P. J.; Hall, D. G.; Friedrich, S.; Citron, M.; Audia, J. E. Robust Central Reduction of Amyloid-β in Humans with an Orally Available, Non-Peptidic β-Secretase Inhibitor J. Neurosci. 2011, 31 (46) 16507-16516