Conformational restriction approach to β-Secretase (BACE1) inhibitors: Effect of a cyclopropane ring to induce an alternative binding mode

Journal of Medicinal Chemistry

Volumn 55, Issue 20, 2012, Pages 8838-8858

  Yonezawa, Shuji ^a,b   Yamamoto, Takahiko ^a   Yamakawa, Hidekuni ^a   Muto, Chie ^a   Hosono, Motoko ^a   Hattori, Kazunari ^a   Higashino, Kenichi ^a   Yutsudo, Takashi ^a   Iwamoto, Hideo ^a   Kondo, Yutaka ^a   Sakagami, Masahiro ^a   Togame, Hiroko ^a   Tanaka, Yoshikazu ^a   Nakano, Toru ^a   Takemoto, Hiroshi ^a   Arisawa, Mitsuhiro ^b   Shuto, Satoshi ^b  

^a SHIONOGI AND CO LTD   (Japan)

^b HOKKAIDO UNIVERSITY   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

1 (3 BROMOPHENYL) 2 (3 ETHOXY 3 OXOPROPANOYL)CYCLOPROPANECARBOXYLIC ACID; 1 (3 BROMOPHENYL) 3 OXABICYCLO[3.1.0]HEXAN 2 ONE; 1 (3 BROMOPHENYL)CYCLOPROPANE 1,2 DICARBOXYLIC ACID; 1 (4 BROMOPHENYL) 2 (3 ETHOXY 3 OXOPROPANOYL) CYCLOPROPANECARBOXYLIC ACID; 1 (4 BROMOPHENYL)CYCLOPROPANE 1,2 DICARBOXYLIC ACID; 1 PHENYLCYCLOPROPANE 1,2 DICARBOXYLIC ACID; 2 (2 (BIS(TERT BUTOXYCARBONYL)AMINO) 1 METHYL 6 OXO 1,6 DIHYDROPYRIMIDIN 4 YL) 1 PHENYLCYCLOPROPANECARBOXYLIC ACID; 2 (3 ETHOXY 3 OXOPROPANOYL) 1 PHENYLCYCLOPROPANECARBOXYLIC ACID; 2 [(TERT BUTYLDIPHENYLSILYLOXY)METHYL] 1 PHENYLCYCLOPROPANECARBOXYLIC ACID; 2 [4'[2 (2 AMINO 1 METHYL 6 OXO 1,6 DIHYDROPYRIMIDIN 4 YL)CYCLOPROPYL]BIPHENYL 3 YL]ACETONITRILE HYDROCHLORIDE; 2 AMINO 3 METHYL 6 (2 PHENYLCYCLOPROPYL)PYRIMIDIN 4(3H) ONE; 2 AMINO 6 (2 PHENYLCYCLOPROPYL)PYRIMIDIN 4(3H) ONE; 2 AMINO 6 [2 (3 BROMOPHENYL)CYCLOPROPYL] 3 METHYLPYRIMIDIN 4(3H) ONE; 2 AMINO 6 [2 (BIPHENYL 3 YL) CYCLOPROPYL] 3 METHYLPYRIMIDIN 4(3H) ONE HYDROCHLORIDE; 2 AMINO 6 [2 (BIPHENYL 3 YL)ETHYL] 3 METHYLPYRIMIDIN 4(3H) ONE; 2 AMINO 6 [2 (BIPHENYL 4 YL)ETHYL] 3 METHYLPYRIMIDIN 4(3H) ONE; 2 AMINO 6 [2 [3' (ETHYLTHIO)BIPHENYL 4 YL]ETHYL] 3 METHYLPYRIMIDIN 4(3H) ONE; 2 BIS(TERT BUTOXYCARBONYL)AMINO 6 (2 (3 BROMOPHENYL) 2 (PYRIDIN 2 YLTHIO)CYCLOPROPYL) 3 METHYLPYRIMIDIN 4(3H) ONE; 2 BIS(TERT BUTOXYCARBONYL)AMINO 6 (3 BROMOPHENETHYL) 3 METHYLPYRIMIDIN 4(3H) ONE; 4' [2 (2 AMINO 1 METHYL 6 OXO 1,6 DIHYDROPYRIMIDIN 4 YL)CYCLOPROPYL]BIPHENYL 3 CARBOXAMIDE HYDROCHLORIDE; AMIDINE; BETA SECRETASE INHIBITOR; CYCLOPROPANE DERIVATIVE; ETHYL 3 OXO 3 ( 2 PHENYLCYCLOPROPYL)PROPANOATE; ETHYLENE; METHYL 2 (2 AMINO 1 METHYL 6 OXO 1,6 DIHYDROPYRIMIDIN 4 YL) 1 PHENYLCYCLOPROPANECARBOXYLATE; METHYL 2 (2 BIS(TERT BUTOXYCARBONYL)AMINO) 1 METHYL 6 OXO 1,6 DIHYDROPYRIMIDIN 4 YL) 1 (3 BROMOPHENYL) CYCLOPROPANECARBOXYLATE; N [4'[2 (2 AMINO 1 METHYL 6 OXO 1,6 DIHYDROPYRIMIDIN 4 YL)CYCLOPROPYL]BIPHENYL 3 YL]ACETAMIDE HYDROCHLORIDE; SODIUM 1 (3 BROMOPHENYL) 2 (HYDROXYMETHYL) CYCLOPROPANECARBOXYLATE; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ARTICLE; CHIRALITY; CONTROLLED STUDY; DERIVATIZATION; DRUG BINDING; DRUG CONFORMATION; STEREOISOMERISM; STRUCTURE ACTIVITY RELATION; X RAY CRYSTALLOGRAPHY;

AMYLOID PRECURSOR PROTEIN SECRETASES; ASPARTIC ACID ENDOPEPTIDASES; CRYSTALLOGRAPHY, X-RAY; CYCLOPROPANES; ENTROPY; ENZYME-LINKED IMMUNOSORBENT ASSAY; FLUORESCENCE; HUMANS; MOLECULAR CONFORMATION; MOLECULAR DOCKING SIMULATION; PROTEIN BINDING; PYRIMIDINES; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84867823781     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm3011405     Document Type: Article

References (75)

1. Hardy, J.; Selkoe, D. J. The amyloid hypothesis of Alzheimers disease: Progress and problems on the road to therapeutics Science 2002, 297, 353-356
2. Gandy, S. The role of cerebral amyloid β accumulation in common forms of Alzheimer disease J. Clin. Invest. 2005, 115, 1121-1129
3. Querfurth, H. W.; LaFeral, F. M. Mechanisms of disease: Alzheimers disease N. Engl. J. Med. 2010, 362, 329-344
4. Alzheimers Association. Alzheimers Disease Facts and Figures. Alzheimers & Dementia; 2011; Vol. 7, Issue 2.
5. Kandalepas, P. C.; Vassar, R. Identification and biology of β-secretase J. Neurochem. 2012, 120 (Suppl. 1) 55-61
6. Yan, R.; Bienkowski, M. J.; Shuck, M. E.; Miao, H.; Tory, M. C.; Pauley, A. M.; Brashler, J. R.; Stratman, N. C.; Mathews, W. R.; Buhl, A. E.; Carter, D. B.; Tomasselli, A. G.; Parodi, L. A.; Heinrikson, R. L.; Gurney, M. E. Membrane-anchored aspartyl protease with Alzheimers disease β-secretase activity Nature 1999, 402, 533-537
7. Sinha, S.; Anderson, J. P.; Barbour, R.; Basi, G. S.; Caccavello, R.; Davis, D.; Doan, M.; Dovey, H. F.; Frigon, N.; Hong, J.; Jacobson-Croak, K.; Jewett, N.; Keim, P.; Knops, J.; Lieberburg, I.; Power, M.; Tan, H.; Tatsuno, G.; Tung, J.; Schenk, D.; Seubert, P.; Suomensaari, S. M.; Wang, S.; Walker, D.; Zhao, J.; McConlogue, L.; John, V. Purification and cloning of amyloid precursor protein β-secretase from human brain Nature 1999, 402, 537-540
8. 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.; Collins, F.; Treanor, J.; Rogers, G.; Citron, M. β-Secretase cleavage of Alzheimers amyloid precursor protein by the transmembrane aspartic protease BACE Science 1999, 286, 735-741
9. Lin, X.; Koelsch, G.; Wu, S.; Downs, D.; Dashti, A.; Tang, J. Human aspartic protease memapsin 2 cleaves the β-secretase site of β-amyloid precursor protein Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 1456-1460
10. 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 Alzheimers β-secretase, have normal phenotype and abolished β-amyloid generation Nature Neurosci. 2001, 4, 231-232
11. Cai, H.; Wang, Y.; McCarthy, D.; Wen, H.; Borchelt, D. R.; Price, D. L.; Wong, P. C. BACE1 is the major β-secretase for generation of Aβ peptides by neurons Nature Neurosci. 2001, 4, 233-234
12. Albert, J. S. Progress in the development of β-secretase Inhibitors for Alzheimers disease Prog. Med. Chem. 2009, 48, 133-161
13. Hamada, Y.; Kiso, Y. Recent progress in the drug discovery of non-peptidic BACE1 inhibitors Expert Opin. Drug. Discovery 2009, 4, 391-416
14. Iserloh, U.; Cumming, J. N. Peptidomimetic BACE1 inhibitors for treatment of Alzheimers disease: design and evolution Methods Princ. Med. Chem. 2010, 45 (Aspartic Acid Proteases as Therapeutic Targets) 441-479
15. Cole, D. C.; Bursavich, M. G. Nonpeptide BACE1 inhibitors: design and synthesis Methods Princ. Med. Chem. 2010, 45 (Aspartic Acid Proteases as Therapeutic Targets) 481-509
16. Ghosh, A. K.; Brindisi, M.; Tang, J. Developing β-secretase inhibitors for treatment of Alzheimers disease J. Neurochem. 2012, 120 (Suppl. 1) 71-83
17. 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, 16507-16516
18. Shitaka, Y.; Mitani, Y.; Nagakura, A.; Miyake, A.; Matsuoka, N. Progress in the development of anti-amyloid drugs for treatment of Alzheimers disease Nippon Yakurigaku Zasshi 2010, 136, 15-20
19. Frisardi, V.; Solfrizzi, V.; Imbimbo, B. P.; Capurso, C.; DIntrono, A.; Colacicco, A. M.; Vendemiale, G.; Seripa, D.; Pilotto, A.; Capurso, A.; Panza, F. Towards disease-modifying treatment of Alzheimers disease: drugs targeting β-amyloid Curr. Alzheimer Res. 2010, 7, 40-55
20. 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, 5903-5911
21. 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, 5912-5925
22. Albert, J. S.; Andisik, D.; Arnold, J.; Brown, D.; Callaghan, O.; Campbell, J.; Carr, R. A.; Chessari, G.; Congreve, M. S.; Edwards, P.; Empfield, J. R.; Frederickson, M.; Koether, G. M.; Krumrine, J.; Mauger, R.; Murray, C. W.; Patel, S.; Sylvester, M.; Throner, S. Preparation of substituted 2-aminopyrimidin-4-ones for treating or preventing Aβ-related pathologies. Patent WO2006041404, WO2006041405, 2006.
23. Cheng, Y.; Judd, T. C.; Bartberger, M. D.; Brown, J.; Chen, K.; Fremeau, R. T.; Hickman, D.; Hitchcock, S. A.; Jordan, B.; Li, V.; Lopez, P.; Louie, S. W.; Luo, Y.; Michelsen, K.; Nixey, T.; Powers, T. S.; Rattan, C.; Sickmier, E. A., St.; Jean, D. J.; Wahl, R. C.; Wen, P. H.; Wood, S. From fragment screening to in vivo efficacy: Optimization of a series of 2-aminoquinolines as potent inhibitors of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) J. Med. Chem. 2011, 50, 5836-5857
24. 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 β-site amyloid cleaving enzyme (BACE) inhibitors: Part I-Inhibitor design and validation J. Med. Chem. 2010, 49, 951-965
25. 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. 2010, 49, 942-950
26. Madden, J.; Dod, J. R.; Godemann, R.; Kraemer, J.; Smith, M.; Biniszkiewicz, M.; Hallett, D. J.; Barker, J.; Dyekjaer, J. D.; Hesterkamp, T. Fragment-based discovery and optimization of BACE1 inhibitors Bioorg. Med. Chem. Lett. 2010, 20, 5329-5333
27. Godemann, R.; Madden, J.; Kraemer, 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
28. Congreve, M.; Aharony, D.; Albert, J. S.; 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, 1124-1132
29. 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, 1116-1123
30. Congreve, M.; Chessari, G.; Tisi, D.; Woodhead, A. J. Recent developments in fragment-based drug discovery J. Med. Chem. 2008, 51, 3661-3680
31. Orita, M.; Ohno, K.; Warizaya, M.; Amano, Y.; Niimi, T. Lead generation and examples: opinion regarding how to follow up hits Methods Enzymol. 2011, 493, 383-419
32. Lovering, F.; Bikker, J.; Humblet, C. Escape from Flatland: Increasing saturation as an approach to improving clinical success J. Med. Chem. 2009, 52, 6752-6756
33. Clemons, P. A.; Bodycombe, N. E.; Carrinski, H. A.; Wilson, J. A.; Shamji, A. F.; Wagner, B. K.; Koehler, A. N.; Schreiber, S. L. Small molecules of different origins have distinct distributions of structural complexity that correlate with protein-binding profiles Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 18787-18792
34. DeLorbe, J. E.; Clements, J. H.; Teresk, M. G.; Benfield, A. P.; Plake, H. R.; Millspaugh, L. E.; Martin, S. F. Thermodynamic and structural effects of conformational constraints in protein-ligand interactions: Entropic paradoxy associated with ligand preorganization J. Am. Chem. Soc. 2009, 131, 16758-16770
35. Benfield, A. P.; Teresk, M. G.; Plake, H. R.; DeLorbe, J. E.; Millspaugh, L. E.; Martin, S. F. Ligand preorganization may be accompanied by entropic penalties in protein-ligand interactions Angew. Chem., Int. Ed. 2006, 45, 6830-6835
36. Davidson, J. P.; Lubman, O.; Rose, T.; Waksman, G.; Martin, S. F. Calorimetric and structural studies of 1,2,3-trisubstituted cyclopropanes as conformationally constrained peptide inhibitors of Src SH2 domain binding J. Am. Chem. Soc. 2002, 124, 205-215
37. Gagnon, A.; Duplessis, M.; Fader, L. Arylcyclopropanes: properties, synthesis and use in medicinal chemistry Org. Prep. Proc. Int. 2010, 42, 1-69
38. Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Stereoselective cyclopropanation reactions Chem. Rev. 2003, 103, 977-1050
39. Shuto, S.; Ono, S.; Hase, Y.; Kamiyama, N.; Takada, H.; Yamasihita, K.; Matsuda, A. Conformational restriction by repulsion between adjacent substituents on a cyclopropane ring: design and enantioselective synthesis of 1-phenyl-2-(1-aminoalkyl)-N,N-diethylcyclopropanecarboxamides as potent NMDA receptor antagonists J. Org. Chem. 1996, 61, 915-923
40. Shuto, S.; Ono, S.; Hase, Y.; Ueno, Y.; Noguchi, T.; Yoshii, K.; Matsuda, A. Synthesis and biological activity of conformationally restricted analogs of milnacipran: (1 S,2 R)-1-phenyl-2-[(S)-1-aminopropyl]- N, N - diethylcyclopropanecarboxamide, an efficient noncompetitive N -methyl- d -aspartic acid receptor antagonist J. Med. Chem. 1996, 52, 6752-6756
41. Ono, S.; Ogawa, K.; Yamashita, K.; Yamamoto, T.; Kazuta, Y.; Matsuda, A.; Shuto, S. Conformational analysis of the NMDA receptor antagonist (1 S,2 R)-1-phenyl-2-[(S)-1-aminopropyl]- N, N -diethylcyclopropanecarboxamide (PPDC) designed by a novel conformational restriction method based on the structural feature of cyclopropane ring Chem. Pharm. Bull. 2002, 50, 966-968 and references therein.
42. Kazuta, Y.; Matsuda, A.; Shuto, S. Development of versatile cis-and trans -dicarbon-substituted chiral cyclopropane units: Synthesis of (1 S,2 R)- and (1 R,2 R)-2-aminomethyl-1-(1 H -imidazol-4-yl)cyclopropanes and their enantiomers as conformationally restricted analogues of histamine J. Org. Chem. 2002, 67, 1669-1677
43. 3 receptor, having a cis -cyclopropane structure J. Med. Chem. 2003, 46, 1980-1988
44. 4 receptor antagonists with an imidazolylcyclopropane structure J. Med. Chem. 2006, 49, 5787-5796
45. 3 receptor antagonists by the cyclopropylic strain-based conformational restriction strategy J. Med. Chem. 2011, 53, 3585-3593
46. Merck molecular force field 94x (MMFF94x force field) is the variant of MMFF94, which improved the treatment of planar nitrogen. Parrill, A. L.; Wanjala, I. W.; Pham, T. C. T.; Baker, D. L. Computational identification and experimental characterization of substrate binding determinants of nucleotide pyrophosphatase/phosphodiesterase 7 BMC Biochem. 2011, 12, 65
47. MMFF VII. Characterization of MMFF94, MMFF94s, and other widely available force fields for conformational energies and for intermolecular interaction energies and geometries. J. Comput. Chem., 1999, 20, 730-748.
48. Ercanli, T; Boyd, D. B. Evaluation of computational chemistry methods: Crystallographic and cheminformatics analysis of aminothiazole methoximes J. Chem. Inf. Model. 2005, 45, 591-601
49. For details of original MMFF94, see: Halgren, T. A. Merck molecular force field. I. Basis, form, scope, parameterization, and performance of MMFF94 J. Comput. Chem. 1996, 17, 490-519
50. Molecular Operating Environment (MOE), 2011.10; Chemical Computing Group Inc., 1010 Sherbooke St. West, Suite #910, Montreal, QC, Canada, H3A 2R7, 2011. URL: http://www.chesemcomp.com/.
51. Yamaguchi, K.; Kazuta, Y.; Abe, H.; Matsuda, A.; Shuto, S. Construction of a cis -cyclopropane via reductive radical decarboxylation. Enantioselective synthesis of cis-and trans -1-arylpiperazyl-2-phenylcyclopropanes designed as antidopaminergic agents J. Org. Chem. 2003, 68, 9255-9262
52. Brooks, D. W.; Lu, L. D. L.; Masamune, S. Carbon acylation under practically neutral conditions Angew. Chem., Int. Ed. Engl. 1979, 18, 72-74
53. Clay, R. J.; Collom, T. A.; Karrick, G. L.; Wemple, J. A safe, economical method for the preparation of β-oxo esters Synthesis 1993, 290-292
54. 4 receptor antagonists as potential antipsychotic agents J. Med. Chem. 2000, 43, 3923-3932
55. Diedrichs, N.; Westermann, B. Synthesis of enantiomerically pure bicyclic lactams Synlett 1999, 1127-1129
56. Oba, M.; Nishiyama, N.; Nishiyama, K. Novel stereocontrolled approach to conformationally constrained analogues of l -glutamic acid and l -proline via stereoselective cyclopropanation of 3,4-didehydro- l -pyroglutamic ABO ester Tetrahedron 2005, 61, 8456-8464
57. For a plausible mechanism for the production of compound 29, see Figure S1 in: Barton, D. H. R.; Crich, D.; Motherwell, W. B. The invention of new radical chain reactions. Part VIII. Radical chemistry of thiohydroxamic esters; A new method for the generation of carbon radicals from carboxylic acids Tetrahedron 1985, 41, 3901-3924
58. Cumming, J. N.; Smith, E. M.; Wang, L.; Misiaszek, J.; Durkin, J.; Pan, J.; Iserloh, U.; Wu, Y.; Zhu, Z.; Strickland, C.; Voigt, J.; Chen, X.; Kennedy, M. E.; Kuvelkar, R.; Hyde, L. A.; Cox, K.; Favreau, L.; Czarniecki, M. F.; Greenlee, W. J.; McKittrick, B. A.; Parker, E. M.; Stamford, A. W. Structure based design of iminohydantoin BACE1 inhibitors: Identification of an orally available, centrally active BACE1 inhibitor Bioorg. Med. Chem. Lett. 2012, 22, 2442-2449
59. Swahn, B.-M.; Holenz, J.; Kihlstroem, J.; Kolmodin, K.; Lindstroem, J.; Plobeck, N.; Rotticci, D.; Sehgelmeble, F.; Sundstroem, M.; Berg, S. v.; Faelting, J.; Georgievska, B.; Gustavsson, S.; Neelissen, J.; Ek, M.; Olsson, L.-L.; Berg, S. Aminoimidazoles as BACE-1 inhibitors: The challenge to achieve in vivo brain efficacy Bioorg. Med. Chem. Lett. 2012, 22, 1854-1859
60. Zhou, P.; Li, Y.; Fan, Y.; Wang, Z.; Chopra, R.; Olland, A.; Hu, Y.; Magolda, R. L.; Pangalos, M.; Reinhart, P. H.; Turner, M. J.; Bard, J.; Malamas, M. S.; Robichaud, A. J. Pyridinyl aminohydantoins as small molecule BACE1 inhibitors Bioorg. Med. Chem. Lett. 2010, 20, 2326-2329
61. Nowak, P.; Cole, D. C.; Aulabaugh, A.; Bard, J.; Chopra, R.; Cowling, R.; Fan, K. Y.; Hu, B.; Jacobsen, S.; Jani, M.; Jin, G.; Lo, M.-C.; Malamas, M. S.; Manas, E. S.; Narasimhan, R.; Reinhart, P.; Robichaud, A. J.; Stock, J. R.; Subrath, J.; Svenson, K.; Turner, J.; Wagner, E.; Zhou, P.; Ellingboe, J. W. Discovery and initial optimization of 5,5′-disubstituted aminohydantoins as potent β-secretase (BACE1) inhibitors Bioorg. Med. Chem. Lett. 2010, 20, 632-635
62. Malamas, M. S.; Robichaud, A.; Erdei, J.; Quagliato, D.; Solvibile, W.; Zhou, P.; Morris, K.; Turner, J.; Wagner, E.; Fan, K.; Olland, A.; Jacobsen, S.; Reinhart, P.; Riddell, D.; Pangalos, M. Design and synthesis of aminohydantoins as potent and selective human β-secretase (BACE1) inhibitors with enhanced brain permeability Bioorg. Med. Chem. Lett. 2010, 20, 6597-6605
63. Malamas, M. S.; Erdei, J.; Gunawan, I.; Turner, J.; Hu, Y.; Wagner, E.; Fan, K.; Chopra, R.; Olland, A.; Bard, J.; Jacobsen, S.; Magolda, R. L.; Pangalos, M.; Robichaud, A. J. Design and synthesis of 5,5′-disubstituted aminohydantoins as potent and selective human β-secretase (BACE1) inhibitors J. Med. Chem. 2010, 53, 1146-1158
64. 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 β-secretase (BACE1) inhibitors J. Med. Chem. 2009, 52, 6314-6323
65. Stachel, S. J.; Coburn, C. A.; Rush, D.; Jones, K. L. G.; Zhu, H.; Rajapakse, H.; Graham, S. L.; Simon, A.; Holloway, M. K.; Allison, T. J.; Munshi, S. K.; Espeseth, A. S.; Zuck, P.; Colussi, D.; Wolfe, A.; Pietrak, B. L.; Lai, M.-T.; Vacca, J. P. Discovery of aminoheterocycles as a novel β-secretase inhibitor class: pH dependence on binding activity part 1 Bioorg. Med. Chem. Lett. 2009, 19, 2977-2980
66. Takahashi, O.; Kohno, Y.; Iwasaki, S.; Saito, K.; Iwaoka, M.; Tomoda, S.; Umezawa, Y.; Tsuboyama, S.; Nishio, M. Hydrogen-bond-like nature of the CH/π interaction as evidenced by crystallographic database analyses and ab initio molecular orbital calculations Bull. Chem. Soc. Jpn. 2001, 74, 2421-2430
67. Nishio, M. CH/π hydrogen bonds in crystals CrystEngComm 2004, 6, 130-158
68. Takahashi, O.; Kohno, Y.; Nishio, M. Relevance of weak hydrogen bonds in the conformation of organic compounds and bioconjugates: evidence from recent experimental data and high-level ab initio MO calculations Chem. Rev. 2010, 110, 6049-6076
69. Tsuzuki, S.; Honda, K.; Uchimaru, T.; Mikami, M.; Tanabe, K. The magnitude of the CH/π interaction between benzene and some model hydrocarbons J. Am. Chem. Soc. 2000, 122, 3746-3753
70. Ran, J.; Wong, M. W. Saturated hydrocarbon-benzene complexes: theoretical study of cooperative CH/π interactions J. Phys. Chem. A 2006, 110, 9702-9709
71. Rotation of the side chain of Leu30 was observed in the complex of BACE1 and its peptidemimetic inhibitor OM00-3: Hong, L.; Turner, R. T., III; Koelsch, G.; Shin, D.; Ghosh, A. K.; Tang, J. Crystal structure of memapsin 2 (β-secretase) in complex with an inhibitor OM00-3 Biochemistry 2001, 41, 10963-10967
72. Otwinowski, Z.; Minor, W. Processing of X-ray diffraction data collected in oscillation mode Methods Enzymol. 1997, 276, 307-326
73. Leslie, A. G. W.; Powell, H. R. Evolving Methods Macromol. Crystallogr. 2007, 245, 41-51, ISBN 978-1-4020-6314-5.
74. Bailey, S. The CCP4 Suite: Programs for protein crystallography Acta Crystallogr. 1994, D50, 760-763
75. Emsley, P.; Lohkamp, B.; Scott, W. G.; Cowtan, K. Features and development of Coot Acta Crystallogr. 2010, D66, 486-501