From fragment screening to in vivo efficacy: Optimization of a series of 2-aminoquinolines as potent inhibitors of beta-site amyloid precursor protein cleaving enzyme 1 (bace1)

Journal of Medicinal Chemistry

Volumn 54, Issue 16, 2011, Pages 5836-5857

  Cheng, Yuan ^a   Judd, Ted C ^a   Bartberger, Michael D ^a   Brown, James ^a   Chen, Kui ^a   Fremeau Jr , Robert T ^a   Hickman, Dean ^b   Hitchcock, Stephen A ^c   Jordan, Brad ^a   Li, Vivian ^a   Lopez, Patricia ^a   Louie, Steven W ^a   Luo, Yi ^a   Michelsen, Klaus ^a   Nixey, Thomas ^a   Powers, Timothy S ^a   Rattan, Claire ^a   Sickmier, E Allen ^a   St Jean Jr , David J ^a   Wahl, Robert C ^a   Wen, Paul H ^a   Wood, Stephen ^a   more..

^a Department of Chemistry Research and Discovery ^*  (United States)

^b AMGEN INC   (United States)

^c Envoy Therapeutics   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 AMINOQUINOLINE; 3 [2 AMINO 6 (3 CHLOROPYRIDIN 2 YL)QUINOLIN 3 YL] N (3,3 DIMETHYLBUTYL) 2 METHYLPROPANAMIDE; AMYLOID BETA PROTEIN; BETA SECRETASE 1; LIGAND; UNCLASSIFIED DRUG;

ANIMAL CELL; ARTICLE; BLOOD BRAIN BARRIER; CEREBROSPINAL FLUID; CONTROLLED STUDY; CRYSTAL STRUCTURE; CRYSTALLIZATION; DRUG EFFICACY; DRUG PENETRATION; DRUG POTENCY; DRUG SCREENING; DRUG SYNTHESIS; ENZYME ACTIVE SITE; HUMAN; HUMAN CELL; IC 50; IN VIVO STUDY; MALE; MOLECULAR MODEL; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION; X RAY CRYSTALLOGRAPHY;

AMINOQUINOLINES; AMYLOID BETA-PEPTIDES; AMYLOID PRECURSOR PROTEIN SECRETASES; ANIMALS; ASPARTIC ACID ENDOPEPTIDASES; BIOCATALYSIS; BRAIN; CATALYTIC DOMAIN; CELL LINE; CRYSTALLOGRAPHY, X-RAY; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG EVALUATION, PRECLINICAL; ENZYME INHIBITORS; HEK293 CELLS; HUMANS; MALE; MODELS, CHEMICAL; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PROTEIN STRUCTURE, TERTIARY; RATS; RATS, SPRAGUE-DAWLEY; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 80051860673     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm200544q     Document Type: Article

References (54)

1. Querfurth, H. W.; LaFeral, F. M. Mechanisms of Disease: Alzheimer's disease N. Engl. J. Med. 2010, 362, 329-344
2. Hardy, J.; Selkoe, D. J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics Science 2002, 297, 353-356 (Pubitemid 34790756)
3. De Strooper, B.; Vasar, R.; Golde, T. The secretases: enzymes with therapeutic potential in Alzheimer's disease Nature Rev. Neurol. 2010, 6, 99-107
4. Vassar, R.; Bennett, B. D.; Babu-Khan, S.; Kahn, S.; Mendiaz, E. A.; Denis, P.; Teplow, D. B.; Ross, S.; Amarante, P.; Loeloff, R.; Luo, Y.; Fisher, S.; Fuller, J.; Edenson, S.; Lile, J.; Jarosinski, M. A.; Biere, A. L.; Curran, E.; Burgess, T.; Louis, J. C. Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE Science 1999, 286, 735-741
5. Vassar, R.; Kovacs, D. M.; Yan, R.; Wong, P. C. The secretase enzyme in health and Alzheimer's disease: regulation, cell biology, function, and therapeutic potential J. Neurosci. 2009, 29, 12787-12794
6. Younkin, S. G. The role of A beta 42 in Alzheimer's disease J. Physiol. (Paris) 1998, 92, 289-292
7. Citron, M. Alzheimer's disease: strategies for disease modification Nature Rev. 2010, 9, 387-398
8. Luo, Y.; Bolon, B.; Kahn, S.; Bennett, B. D.; Babu-Khan, S.; Denis, P.; Fan, W.; Kha, H.; Zhang, J.; Gong, Y.; Martin, L.; Louis, J.-C.; Yan, Q.; Richards, W. G.; Citron, M.; Vassar, R. Mice deficient in BACE1, the Alzheimer's beta-secretase, have normal phenotype and abolished beta-amyloid generation Nature Neurosci. 2001, 4, 231-232 (Pubitemid 32194866)
9. Roberds, S. L.; Anderson, J.; Basi, G.; Bienkowski, M. J.; Branstetter, D. G.; Chen, K. S.; Freedman, S. B.; Frigon, N. L.; Games, D.; Hu, K.; Johnson-Wood, K.; Kappenman, K. E.; Kawabe, T. T.; Kola, I.; Kuehn, R.; Lee, M.; Liu, W.; Motter, R.; Nichols, N. F.; Power, M.; Robertson, D. W.; Schenk, D.; Schoor, M.; Shopp, G. M.; Shuck, M. E.; Sinha, S.; Svensson, K. A.; Tatsuno, G.; Tintrup, H.; Wijsman, J.; Wright, S.; McConlogue, L. BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer's disease therapeutics Hum. Mol. Genet. 2001, 10, 1317-1324 (Pubitemid 32600485)
10. Ohno, M.; Sametsky, E. A.; Younkin, L. H.; Oakley, H.; Younkin, S. G.; Citron, M.; Vassar, R.; Disterhoft, J. F. BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer's disease Neuron 2004, 41, 27-33 (Pubitemid 38071826)
11. McConlogue, L.; Buttini, M.; Anderson, J. P.; Brigham, E. F.; Chen, K. S.; Freedman, S. B.; Games, D.; Johnson-Wood, K.; Lee, M.; Zeller, M.; Liu, W.; Motter, R.; Sinha, S. Partial reduction of BACE1 has dramatic effects on Alzheimer plaque and synaptic pathology in APP transgenic mice J. Biol. Chem. 2007, 282, 26326-26334 (Pubitemid 47443774)
12. Hitchcock, S. A.; Pennington, L. D. Structure-brain exposure relationships J. Med. Chem. 2006, 49, 7559-7583 (Pubitemid 46033646)
13. Clark, D. E. Rapid calculation of polar molecular surface area and its application to the prediction of transport phenomena. 2. Prediction of blood-brain barrier phenetration J. Pharm. Sci. 1999, 88, 815-821 (Pubitemid 29398551)
14. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings Adv. Drug Delivery Rev. 2001, 46, 3-26 (Pubitemid 33653411)
15. Zhong, W.; Hitchcock, S. A.; Albrecht, B. K.; Bartberger, M.; Brown, J.; Brown, R.; Chaffee, S. C.; Cheng, Y.; Croghan, M.; Graceffa, R.; Harried, S.; Hickman, D.; Horne, D.; Hungate, R.; Judd, T.; Kaller, M.; Kreiman, C.; La, D.; Lopez, P.; Masse, C. E.; Monenschein, H.; Nguyen, T.; Nixey, T.; Patel, V. F.; Pennington, L.; Weiss, M.; Xue, Q.; Yang, B. Preparation of 2-hydroxy-1,3- diaminoalkanes including spiro substituted chroman derivatives as secretase modulators and their use for treatment Alzheimer's disease and related condition. Patent WO2007061670, 2007.
16. 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 (secretase) inhibitors with isophthalamide derivatives as the P2-P3-ligands J. Med. Chem. 2007, 50, 2399-2407 (Pubitemid 46799251)
17. 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 secretase J. Med. Chem. 2007, 50, 776-781 (Pubitemid 46332990)
18. Ghosh, A. K.; Kumaragurubaran, N.; Tang, J. Recent developments of structure-based secretase inhibitors for Alzheimer's disease Curr. Top. Med. Chem. 2005, 5, 1609-1622
19. Silvestri, R. Boom in the development of non-peptidic beta-secretase (BACE1) inhibitors for the treatment of Alzheimer's disease Med. Res. Rev. 2009, 29, 295-338
20. Hamada, Y.; Kiso, Y. Recent progress in the drug discovery of non-peptidic BACE1 inhibitors Expert Opin. Drug Discovery 2009, 4, 391-416 and references therein
21. Malamas, M. S.; Erdei, J.; Gunawan, I.; Turner, J.; Hu, Y.; Wagner, E.; Fan, K.; Chopra, R.; Olland, A.; Bard, J.; Jocobsen, S.; Magolda, R. L.; Pangalos, M.; Robichaud, A. J. Design and synthesis of 5,5-disubstituted aminohydantoins as potent and selective human secretase (BACE1) inhibitor J. Med. Chem. 2010, 53, 1146-1158
22. Malamas, M. S.; Erdei, J.; Gunawan, I.; Barnes, K.; Johnson, M.; Hui, Y.; Turner, J.; Hu, Y.; Wagner, E.; Fan, K.; Olland, A.; Bard, J.; Robichaud, A. J. Aminoimidazoles as potent and selective human -secretase (BACE1) inhibitors J. Med. Chem. 2009, 52, 6314-6323
23. Zhu, Z.; Sun, Z.-Y.; Ye, Y.; Voigt, J.; Strickland, C.; Smith, E. M.; Cumming, J.; Wang, L.; Wong, J.; Wang, Y.-S.; Wyss, D. F.; Chen, X.; Kuvelkar, R.; Kennedy, M. E.; Favreau, L.; Parker, E.; McKittrick, B. A.; Stamford, A.; Czarniecki, M.; Greenlee, W.; Hunter, J. C. Discovery of cyclic acylguanidines as highly potent and selective site amyloid cleaving enzyme (BACE) inhibitors: Part I: Inhibitor design and validation J. Med. Chem. 2010, 53, 951-965
24. 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 (site APP cleaving enzyme): use of structure based design to convert a micromolar hit into a nanomolar lead J. Med. Chem. 2007, 50, 4261-4264 (Pubitemid 47378825)
25. Orita, M.; Warizaya, M.; Amano, Y.; Ohno, K.; Niimi, T. Advances in fragment-based drug discovery platforms Curr. Opin. Pharmacol. 2009, 9, 615-621
26. Eitner, K.; Koch, U. From fragment screening to potent binders: strategies for fragment-to-lead evolution Mini-Rev. Med. Chem. 2009, 9, 956-961
27. Chessari, G.; Woodhead, A. J. From fragment to clinical candidate-a historical perspective Drug Discovery Today 2009, 14, 668-675
28. Fattori, D.; Squarcia, A.; Bartoli, S. Fragment-based approach to drug lead discovery: overview and advances in various techniques Drugs R&D 2008, 9, 217-227 (Pubitemid 351920121)
29. Wyss, D. F.; Eaton, H. L. Fragment-based approaches to lead discovery Front. Drug Des. Discovery 2007, 3, 171-202
30. Reynolds, C. H.; Tounge, B. A.; Bembenek, S. D. Ligand binding efficiency: trends, physical basis, and implications J. Med. Chem. 2008, 51, 2432-2438 (Pubitemid 351628504)
31. Abad-Zapatero, C. Ligand efficiency indices for effective drug discovery Expert Opin. Drug Discovery 2007, 2, 469-488 (Pubitemid 47073073)
32. 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 (Site APP Cleaving Enzyme 1) Inhibitors J. Med. Chem. 2010, 53, 942-950
33. Godemann, R.; Madden, J.; Kramer, J.; Smith, M.; Fritz, U.; Hesterkamp, T.; Barker, J.; Hoeppner, S.; Hallett, D.; Cesura, A.; Ebneth, A.; Kemp, J. Fragment-based discovery of BACE1 inhibitors using functional assays Biochemistry 2009, 48, 10743-10751
34. Yang, W.; Fucini, R. V.; Fahr, B. T.; Randal, M.; Lind, K. E.; Lam, M. B.; Lu, W.; Lu, Y.; Cary, D. R.; Romanowski, M. J.; Colussi, D.; Pietrak, B.; Allison, T. J.; Munshi, S. K.; Penny, D. M.; Pham, P.; Sun, J.; Thomas, A. E.; Wilkinson, J. M.; Jacobs, J. W.; McDowell, R. S.; Ballinger, M. D. Fragment-Based Discovery of Nonpeptidic BACE-1 Inhibitors Using Tethering Biochemistry 2009, 48, 4488-4496
35. Albert, J. S.; Blomberg, N.; Breeze, A. L.; Brown, A. J. H.; Burrows, J. N.; Edwards, P. D.; Folmer, R. H. A.; Geschwindner, S.; Griffen, E. J.; Kenny, P. W.; Nowak, T.; Olsson, L.-L.; Sanganee, H.; Shapiro, A. B. An integrated approach to fragment-based lead generation: philosophy, strategy and case studies from AstraZeneca's drug discovery programs Curr. Top. Med. Chem. 2007, 7, 1600-1629 (Pubitemid 350131017)
36. 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 secretase inhibitors with nanomolar potency, cellular activity, and high ligand efficiency J. Med. Chem. 2007, 50, 5912-5925
37. 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 Secretase through Fragment-Based Lead Generation J. Med. Chem. 2007, 50, 5903-5911
38. 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 secretase J. Med. Chem. 2007, 50, 1116-1123 (Pubitemid 46496312)
39. 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 secretase J. Med. Chem. 2007, 50, 1124-1132 (Pubitemid 46496313)
40. Huber, W.; Mueller, F. Biomolecular interaction analysis in drug discovery using surface plasmon resonance technology Curr. Pharm. Des. 2006, 12, 2999-4021
41. Huber, W. A new strategy for improved secondary screening and lead optimization using high-resolution SPR characterization of compound-target interactions J. Mol. Recognit. 2005, 18, 273-281 (Pubitemid 41059724)
42. Meth-Cohn, O.; Narine, B.; Tarnowski, B. A versatile new synthesis of quinolines and related fused pyridines. Part 5. The synthesis of 2-chloroquinoline-3-carboxaldehydes J. Chem. Soc., Perkin Trans. 1 1981, 5, 1520-1530
43. Wang, Q.; Rager, J. D.; Weinstein, K.; Kardos, P. S.; Dobson, G. L.; Li, J.; Hidalgo, I. J. Evaluation of the MDR-MECK cell line as a permeability screen for the blood-brain barrier Int. J. Pharm. 2005, 288, 349-359 (Pubitemid 40038588)
44. Liu, X.; Chen, C. Strategies to optimize brain penetration in drug discovery Curr. Opin. Drug Discovery Dev. 2005, 8, 505-512 (Pubitemid 40917412)
45. Wong, G. T.; Manfra, D.; Poulet, F. M.; Zhang, Q.; Josien, H.; Bara, T.; Engstrom, L.; Pinzon-Ortiz, M.; Fine, J. S.; Lee, H. J.; Zhang, L.; Higgins, G. A.; Parker, E. M. Chronic treatement with the secretase inhibitor LY-411,575 inhibits amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation J. Biol. Chem. 2004, 279, 12876-12882 (Pubitemid 38445862)
46. Turner, R. T., III; Koelsch, G.; Hong, L.; Castanheira, P.; Ghosh, A.; Tang, J. Subsite specificity of memapsin (secretase): implications for inhibitor design Biochemistry 2001, 40, 10001-10006 (Pubitemid 32800106)
47. Haniu, M.; Denis, P.; Young, Y.; Mendiaz, E. A.; Fuller, J.; Hui, J. O.; Bennett, B. D.; Kahn, S.; Ross, S.; Burgess, T. Characterization of Alzheimer's beta-secretase protein BACE. A pepsin family member with unusual properties J. Biol. Chem. 2000, 275, 21099-21106 (Pubitemid 30481802)
48. Schinkel, A. H.; Wagenaar, E.; van Deemter, L.; Mol, C. A. A. M.; Borst, P. Absence of the mdr1a P-glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A J. Clin. Invest. 1995, 96, 1698-1705
49. Booth-Genthe, C. L.; Louie, S. W.; Carlini, E. J.; Li, B.; Leake, B. F.; Eisenhandler, R.; Hochman, J. H.; Mei, Q.; Kim, R. B.; Rushmore, T. H.; Yamazaki, M. Development and characterization of LLC-PK1 cells containing Sprague-Dawley rat Abcb 1a (Mdr 1a): Comparison of rat P-glycoprotein transport to human and mouse J. Pharmacol. Toxicol. Methods 2006, 54, 78-89 (Pubitemid 43975019)
50. Patel, S.; Vuillard, L.; Cleasby, A.; Murray, C. W.; Yon, J. Apo and inhibitor complex structures of BACE (beta-secretase) J. Mol. Biol. 2004, 343, 407-416 (Pubitemid 39296874)
51. Otwinowski, Z.; Minor, W. Processing of X-ray diffraction data collected in oscillation mode Methods Enzymol. 1997, 276, 307-326 (Pubitemid 27085611)
52. McCoy, A. J.; Grosse-Kunstleve, R. W.; Adams, P. D.; Winn, M. D.; Storoni, L. C.; Read, R. J. Phaser crystallographic software J. Appl. Crystallogr. 2007, 40, 658-674 (Pubitemid 47080256)
53. Murshudov, G. N.; Vagin, A. A.; Dodson, E. J. Refinement of macromolecular structures by the maximum-likelihood method Acta Crystallogr., Sect. D: Biol. Crystallogr. 1997, D53, 240-255 (Pubitemid 27235885)
54. Emsley, P.; Cowtan, K. Coot: model-building tools for molecular graphics Acta Crystallogr., Sect. D: Biol. Crystallogr. 2004, D60, 2126-2132 (Pubitemid 41742764)