Utilizing Structures of CYP2D6 and BACE1 Complexes to Reduce Risk of Drug-Drug Interactions with a Novel Series of Centrally Efficacious BACE1 Inhibitors

Journal of Medicinal Chemistry

Volumn 58, Issue 7, 2015, Pages 3223-3252

  Brodney, Michael A ^a   Beck, Elizabeth M ^a   Butler, Christopher R ^a   Barreiro, Gabriela ^a   Johnson, Eric F ^b   Riddell, David ^a   Parris, Kevin ^a   Nolan, Charles E ^a   Fan, Ying ^b   Atchison, Kevin ^a   Gonzales, Cathleen ^a   Robshaw, Ashley E ^a   Doran, Shawn D ^a   Bundesmann, Mark W ^a   Buzon, Leanne ^a   Dutra, Jason ^a   Henegar, Kevin ^a   LaChapelle, Erik ^a   Hou, Xinjun ^a   Rogers, Bruce N ^a   Pandit, Jayvardhan ^a   Lira, Ricardo ^a   Martinez Alsina, Luis ^a   Mikochik, Peter ^a   Murray, John C ^a   Ogilvie, Kevin ^a   Price, Loren ^a   Sakya, Subas M ^a   Yu, Aijia ^c   Zhang, Yong ^c   O'Neill, Brian T ^a   more..

^a PFIZER INC   (United States)

^b SCRIPPS RESEARCH INSTITUTE   (United States)

^c WUXI APPTEC   (China)

Author keywords

[No Author keywords available]

Indexed keywords

1 (BENZYLOXY) 6 [(TETRAHYDRO 2H PYRAN 2 YL)OXY]HEX 4 YN 2 OL; 1 (BENZYLOXY)HEX 4 EN 2 OL; 1 (BENZYLOXY)HEX 4 YN 2 OL; 2 (BENZOYLAMINO) 8A (2,4 DIFLUOROPHENYL) 4 METHYL 4,4A,5,6,8,8A HEXAHYDROPYRANO[3,4 D][1,3] THIAZINE 6 CARBOXYLIC ACID; 2 [[1 (BENZYLOXY) 6 HYDROXYHEX 4 EN 2 YL]OXY]ACETALDEHYDE OXIME; 2 [[1 (BENZYLOXY)HEX 4 EN 2 YL]OXY] N HYDROXYETHANIMINE; 2 [[6 (BENZYLOXY) 5 (2,2 DIETHOXYETHOXY)HEX 2 YN 1 YL]OXY]TETRAHYDRO 2H PYRAN; 5 [(BENZYLOXY)METHYL] 3 METHYL 3,3A,4,5 TETRAHYDRO 7H PYRANOL[3,4 C]OXAZOLE; 6 (BENZYLOXY) 5 (2,2 DIETHOXYETHOXY)HEX 2 EN 1 OL; 6 (BENZYLOXY) 5 (2,2 DIETHOXYETHOXY)HEX 2 YN 1 OL; 8A (2,4 DIFLUOROPHENYL) 4 (FLUOROMETHYL) 6 (1 METHYL 1H PYRAZOL 4 YL) 4,4A,5,6,8,8A HEXAHYDROPYRANO[3,4 D][1,3]THIAZIN 2 AMINE; 8A (2,4 DIFLUOROPHENYL) 4 (FLUOROMETHYL) 6 (3 METHYL 1,2 OXAZOL 1 5 YL) 4,4A,5,6,8,8A HEXAHYDROPYRANO[3,4 D][1,3]THIAZINE 2 AMINE; 8A (2,4 DIFLUOROPHENYL) 4 (FLUOROMETHYL) 6 (3 METHYL 1,2 OXAZOL 5 YL) 4,4A,5,6,8,8A HEXAHYDROPYRANO[3,4 D][1,3]THIAZINE 2 AMINE; 8A (2,4 DIFLUOROPHENYL) 4 (FLUOROMETHYL) 6 (4 METHYLOXAZOL 2 YL) 4,4A,5,6,8,8A HEXAHYDROPYRANO[3,4 D][1,3]THIAZINE 2 AMINE; 8A (2,4 DIFLUOROPHENYL) 4 METHYL 6 (1 METHYL 1H PYRAZOL 4 YL) 4,4A,5,6,8,8A HEXAHYDROPYRANO[3,4 D][1,3]THIAZIN 2 AMINE; 8A (2,4 DIFLUOROPHENYL) 4 METHYL 6 (4 METHYL OXAZOL 2 YL) 4,4A,5,6,8,8A HEXAHYDROPYRANO[3,4 D][1,3]THIAZIN 2 AMINE; 8A (2,4 DIFLUOROPHENYL) 4,4A,5,6,8,8A HEXAHYDROPYRANO[3,4 D][1,3]THIAZIN 6 CARBOXYLIC ACID; 8A (2,4 DIFUOROPHENYL) 4 METHYL 6 (3 METHYL 1,2 OXAZOL 5 YL) 4,4A,5,6,8,8A HEXAHYDROPYRANOL[3,4 D][1,3]THIAZIN 2 AMINE; 8A (2,4 DIFUOROPHENYL) 6 (1 METHYL 1H PYRAZOL 4 YL) 4,4A,5,6,8,8A HEXAHYDROPYRANO[3,4 D][1,3]THIAZINE 2 AMINE; 8A (2,4 DIFUOROPHENYL) 6 (1H PYRAZOL 4 YL) 4,4A,5,6,8,8A HEXAHYDROPYRANO[3,4 D][1,3]THIAZINE 2 AMINE; BETA SECRETASE 1; BETA SECRETASE INHIBITOR; CYTOCHROME P450 2D6; N [8A (2,4 DIFLUOROPHENYL) 4 (FLUOROMETHYL) 6 (1,1,3,3 TETRAMETHOXYPROPAN 2 YL) 4,4A,5,6,8,8A HEXAHYDROPYRANO[3,4 D][1,3]THIAZIN 2 YL]BENZAMIDE; N [8A (2,4 DIFLUOROPHENYL) 4 (FLUOROMETHYL) 6 (2 METHOXYETHENYL) 4,4A,5,6,8,8A HEXAHYDROPYRANO[3,4 D][1,3]THIAZIN 2 YL]BENZAMIDE; N [8A (2,4 DIFLUOROPHENYL) 4 (FLUROMETHYL) 6 FORMYL 4,4A,5,6,8,8A HEXAHYDROPYRANO[3,4 D][1,3]THIAZIN 2 YL]BENZAMIDE; N [8A (2,4 DIFLUOROPHENYL) 4 (FORMYL) 4 METHYL 4,4A,5,6,8,8A HEXAHYDROPYRANO[3,4 D][1,3]THIAZIN 2 YL]BENZAMIDE; POTASSIUM CHANNEL HERG; PYRROLE DERIVATIVE; UNCLASSIFIED DRUG; UNINDEXED DRUG; AMYLOID PROTEIN; ASPARTIC PROTEINASE; BACE1 PROTEIN, HUMAN; ERG1 POTASSIUM CHANNEL; PROTEINASE INHIBITOR; PYRAZOLE; PYRAZOLE DERIVATIVE; SECRETASE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CENTRAL NERVOUS SYSTEM; CONTROLLED STUDY; CRYSTAL STRUCTURE; DRUG BRAIN LEVEL; DRUG CLEARANCE; DRUG DESIGN; DRUG EFFICACY; DRUG INTERACTION; DRUG METABOLISM; DRUG PENETRATION; DRUG POTENCY; DRUG SAFETY; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; HUMAN; HUMAN CELL; HYDROGEN BOND; IC50; IN VITRO STUDY; IN VIVO STUDY; LIPOPHILICITY; LIVER MICROSOME; MALE; MOUSE; NONHUMAN; RAT; AMINO ACID SEQUENCE; ANIMAL; ANTAGONISTS AND INHIBITORS; CHEMICAL STRUCTURE; CHEMISTRY; GENETICS; INBRED MOUSE STRAIN; METABOLISM; MOLECULAR GENETICS; STRUCTURE ACTIVITY RELATION; X RAY CRYSTALLOGRAPHY;

AMINO ACID SEQUENCE; AMYLOID PRECURSOR PROTEIN SECRETASES; AMYLOIDOGENIC PROTEINS; ANIMALS; ASPARTIC ACID ENDOPEPTIDASES; CRYSTALLOGRAPHY, X-RAY; CYTOCHROME P-450 CYP2D6; DRUG DESIGN; DRUG INTERACTIONS; ETHER-A-GO-GO POTASSIUM CHANNELS; HUMANS; INHIBITORY CONCENTRATION 50; MALE; MICE, INBRED STRAINS; MODELS, MOLECULAR; MOLECULAR SEQUENCE DATA; PROTEASE INHIBITORS; PYRAZOLES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84927586678     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.5b00191     Document Type: Article

References (59)

1. Hardy, J.; Allsop, D. Amyloid deposition as the central event in the aetiology of Alzheimer's disease Trends Pharmacol. Sci. 1991, 12 (10) 383
2. Walsh, D. M.; Minogue, A. M.; Sala Frigerio, C.; Fadeeva, J. V.; Wasco, W.; Selkoe, D. J. The APP family of proteins: similarities and differences Biochem. Soc. Trans. 2007, 35 (2) 416 - 420
3. Tanzi, R. E.; Bertram, L. Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective Cell 2005, 120 (4) 545 - 555
4. De Strooper, B. Proteases and proteolysis in Alzheimer disease: a multifactorial view on the disease process Physiol. Rev. 2010, 90 (2) 465 - 494
5. Vassar, R.; Kovacs, D. M.; Yan, R.; Wong, P. C. The beta-secretase enzyme BACE in health and Alzheimer's disease: regulation, cell biology, function, and therapeutic potential J. Neurosci. 2009, 29 (41) 12787 - 12794
6. Marks, N.; Berg, M. J. BACE and gamma-secretase characterization and their sorting as therapeutic targets to reduce amyloidogenesis Neurochem. Res. 2010, 35 (2) 181
7. Citron, M.; Eckman, C. B.; Diehl, T. S.; Corcoran, C.; Ostaszewski, B. L.; Xia, W.; Levesque, G.; St. George Hyslop, P.; Younkin, S. G.; Selkoe, D. J. Additive effects of PS1 and APP mutations on secretion of the 42-residue amyloid β-protein Neurobiol. Dis. 1998, 5 (2) 107 - 116
8. Jonsson, T.; Atwal, J. K.; Steinberg, S.; Snaedal, J.; Jonsson, P. V.; Bjornsson, S.; Stefansson, H.; Sulem, P.; Gudbjartsson, D.; Maloney, J.; Hoyte, K.; Gustafson, A.; Liu, Y.; Lu, Y.; Bhangale, T.; Graham, R. R.; Huttenlocher, J.; Bjornsdottir, G.; Andreassen, O. A.; Joensson, E. G.; Palotie, A.; Behrens, T. W.; Magnusson, O. T.; Kong, A.; Thorsteinsdottir, U.; Watts, R. J.; Stefansson, K. A mutation in APP protects against Alzheimer's disease and age-related cognitive decline Nature 2012, 488 (7409) 96 - 99
9. Yuan, J.; Venkatraman, S.; Zheng, Y.; McKeever, B. M.; Dillard, L. W.; Singh, S. B. Structure-based design of beta-site APP cleaving enzyme 1 (BACE1) inhibitors for the treatment of Alzheimer's disease J. Med. Chem. 2013, 56 (11) 4156 - 4180
10. Fielden, M. R.; Werner, J.; Coppi, A.; Dunn, R. T., II; Trueblood, E.; Afshari, C. A.; Lightfoot-Dunn, R.; Jamison, J. A.; Hickman, D.; Zhou, L., Retinal Toxicity Induced by a Novel β-Secretase Inhibitor in the Sprague-Dawley Rat. Toxicol. Pathol. 2014, 0192623314553804.
11. 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.; Smith Labell, E.; Gonzales, C. R.; Nakano, M.; Jhee, S. S.; Yen, M.; Ereshefsky, L.; Lindstrom, T. D.; Calligaro, D. O.; Cocke, P. J.; Greg Hall, D.; Friedrich, S.; Citron, M.; Audia, J. E. Robust central reduction of amyloid-beta in humans with an orally available, non-peptidic beta-secretase inhibitor J. Neurosci. 2011, 31 (46) 16507 - 16516
12. Lilly Voluntarily Terminates Phase II Study for LY2886721, a Beta Secretase Inhibitor, Being Investigated as a Treatment for Alzheimer's Disease; Eli Lilly Pharmaceuticals: Indianapolis, IN, June 13, 2013; https://investor.lilly.com/releaseDetail.cfm?ReleaseID=771353.
13. Butler, C. R.; Brodney, M. A.; Beck, E. M.; Barreiro, G.; Nolan, C. E.; Pan, F.; Vajdos, F.; Parris, K.; Varghese, A. H.; Helal, C. J.; Lira, R.; Doran, S.; Riddell, D. R.; Buzon, L. M.; Dutra, J. K.; Martinez-Alsina, L. A.; Ogilvie, K.; Murray, J. C.; Young, J. M.; Atchison, K.; Robshaw, A.; Gonzales, C.; Wang, J.; Zhang, Y.; O'Neill, B. T., Discovery of a Series of Efficient, Centrally Efficacious BACE1 Inhibitors through Structure-Based Drug Design. J. Med. Chem. 2015, 58, 2678 - 2702, DOI: 10.1021/jm501833t.
14. Stepan, A. F.; Walker, D. P.; Bauman, J.; Price, D. A.; Baillie, T. A.; Kalgutkar, A. S.; Aleo, M. D. Structural alert/reactive metabolite concept as applied in medicinal chemistry to mitigate the risk of idiosyncratic drug toxicity: a perspective based on the critical examination of trends in the top 200 drugs marketed in the United States Chem. Res. Toxicol. 2011, 24 (9) 1345 - 410
15. Freeman-Cook, K. D.; Hoffman, R. L.; Johnson, T. W. Lipophilic efficiency: the most important efficiency metric in medicinal chemistry Future Med. Chem. 2013, 5 (2) 113 - 115
16. Hitchcock, S. A. Structural modifications that alter the P-glycoprotein efflux properties of compounds J. Med. Chem. 2012, 55 (11) 4877 - 4895
17. Lu, Y.; Riddell, D.; Hajos-Korcsok, E.; Bales, K.; Wood, K. M.; Nolan, C. E.; Robshaw, A. E.; Zhang, L.; Leung, L.; Becker, S. L.; Tseng, E.; Barricklow, J.; Miller, E. H.; Osgood, S.; O'Neill, B. T.; Brodney, M. A.; Johnson, D. S.; Pettersson, M. Cerebrospinal fluid amyloid-β (Aβ) as an effect biomarker for brain Aβ lowering verified by quantitative preclinical analyses J. Pharmacol. Exp. Ther. 2012, 342 (2) 366 - 375
18. Rendic, S.; Di Carlo, F. J. Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers, and inhibitors Drug Metab. Rev. 1997, 29 (1,2) 413 - 580
19. Teh, L. K.; Bertilsson, L. Pharmacogenomics of CYP2D6: molecular genetics, interethnic differences and clinical importance Drug Metab. Pharmacokinet. 2012, 27 (1) 55 - 67
20. Bertilsson, L.; Dahl, M.-L.; Dalen, P.; Al-Shurbaji, A. Molecular genetics of CYP2D6: clinical relevance with focus on psychotropic drugs Br. J. Clin. Pharmacol. 2002, 53 (2) 111 - 122
21. Wang, A.; Savas, U.; Hsu, M.-H.; Stout, C. D.; Johnson, E. F. Crystal structure of human cytochrome P 450 2D6 with prinomastat bound J. Biol. Chem. 2012, 287 (14) 10834 - 10843
22. Sanguinetti, M. C.; Tristani-Firouzi, M. hERG potassium channels and cardiac arrhythmia Nature 2006, 440 (7083) 463 - 469
23. Sanguinetti, M. C.; Jiang, C.; Curran, M. E.; Keating, M. T. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel Cell 1995, 81 (2) 299 - 307
24. Roden, D. M. Drug-induced prolongation of the QT interval N. Engl. J. Med. 2004, 350 (10) 1013 - 1022
25. Waring, M. J.; Johnstone, C. A quantitative assessment of hERG liability as a function of lipophilicity Bioorg. Med. Chem. Lett. 2007, 17 (6) 1759 - 1764
26. Ginman, T.; Viklund, J.; Malmstroem, J.; Blid, J.; Emond, R.; Forsblom, R.; Johansson, A.; Kers, A.; Lake, F.; Sehgelmeble, F.; Sterky, K. J.; Bergh, M.; Lindgren, A.; Johansson, P.; Jeppsson, F.; Faelting, J.; Gravenfors, Y.; Rahm, F. Core Refinement toward Permeable β-Secretase (BACE-1) Inhibitors with Low hERG Activity J. Med. Chem. 2013, 56 (11) 4181 - 4205
27. Jamieson, C.; Moir, E. M.; Rankovic, Z.; Wishart, G. Medicinal chemistry of hERG optimizations: highlights and hang-ups J. Med. Chem. 2006, 49 (17) 5029 - 5046
28. Price, D. A.; Armour, D.; de Groot, M.; Leishman, D.; Napier, C.; Perros, M.; Stammen, B. L.; Wood, A. Overcoming hERG affinity in the discovery of maraviroc; a CCR5 antagonist for the treatment of HIV Curr. Top. Med. Chem. 2008, 8 (13) 1140 - 1151
29. Morgenthaler, M.; Schweizer, E.; Hoffmann-Roder, A.; Benini, F.; Martin, R. E.; Jaeschke, G.; Wagner, B.; Fischer, H.; Bendels, S.; Zimmerli, D.; Schneider, J.; Diederich, F.; Kansy, M.; Muller, K. Predicting and tuning physicochemical properties in lead optimization: amine basicities ChemMedChem 2007, 2 (8) 1100 - 1115
30. Motoki, T.; Takeda, K.; Kita, Y.; Takaishi, M.; Suzuki, Y.; Ishida, T. Preparation of novel fused aminodihydrothiazine derivatives as β-secretase 1 (BACE 1) inhibitors. WO2010038686A1, 2010.
31. Morwick, T.; Hrapchak, M.; DeTuri, M.; Campbell, S. A Practical Approach to the Synthesis of 2,4-Disubstituted Oxazoles from Amino Acids Org. Lett. 2002, 4 (16) 2665 - 2668
32. Kim, K. S.; Kimball, S. D.; Misra, R. N.; Rawlins, D. B.; Hunt, J. T.; Xiao, H.-Y.; Lu, S.; Qian, L.; Han, W.-C.; Shan, W.; Mitt, T.; Cai, Z.-W.; Poss, M. A.; Zhu, H.; Sack, J. S.; Tokarski, J. S.; Chang, C. Y.; Pavletich, N.; Kamath, A.; Humphreys, W. G.; Marathe, P.; Bursuker, I.; Kellar, O. K. A.; Roongta, U.; Batorsky, R.; Mulheron, J. G.; Bol, D.; Fairchild, C. R.; Lee, F. Y.; Webster, K. R. Discovery of Aminothiazole Inhibitors of Cyclin-Dependent Kinase 2: Synthesis, X-ray Crystallographic Analysis, and Biological Activities J. Med. Chem. 2002, 45 (18) 3905 - 3927
33. Cooper, J. P.; Cobb, J. E.; Shearer, B. G.; Minick, D. J.; Rutkowske, R. D. Synthesis and identification of a novel 6,5,6-tricyclic lactam Heterocycles 2003, 60 (3) 607 - 613
34. Nitz, T. J.; Volkots, D. L.; Aldous, D. J.; Oglesby, R. C. Regiospecific Synthesis of 3-Substituted 5-Alkylisoxazoles from Oxime Dianions and N -Methoxy- N -Methylalkylamides J. Org. Chem. 1994, 59 (19) 5828 - 5832
35. O'Sullivan, P. T.; Buhr, W.; Fuhry, M. A. M.; Harrison, J. R.; Davies, J. E.; Feeder, N.; Marshall, D. R.; Burton, J. W.; Holmes, A. B. A concise synthesis of the octalactins J. Am. Chem. Soc. 2004, 126 (7) 2194 - 2207
36. Werner, A.; Sanchez-Migallon, A.; Fruchier, A.; Elguero, J.; Fernandez-Castano, C.; Foces-Foces, C. Porphyrins with four azole substituents in meso positions: X-ray crystal structure of meso -tetrakis-(1-benzylpyrazol-4-yl)porphyrin at 200 K Tetrahedron 1995, 51 (16) 4779 - 4800
37. Alberti, C.; Zerbi, G. Synthesis of alkylpyrazoles Farmaco Sci. 1961, 16, 527 - 539
38. Tius, M. A.; Reddy, N. K. Cembrane synthesis. An advanced intermediate for crassin acetate Tetrahedron Lett. 1991, 32 (30) 3605 - 3608
39. Williams, D. R.; Harigaya, Y.; Moore, J. L.; D'Sa, A. Stereocontrolled transformations of orthoester intermediates into substituted tetrahydrofurans J. Am. Chem. Soc. 1984, 106 (9) 2641 - 2644
40. Middleton, W. J. New fluorinating reagents. Dialkylaminosulfur fluorides J. Org. Chem. 1975, 40 (5) 574 - 578
41. Singh, R. P.; Shreeve, J. M. Recent advances in nucleophilic fluorination reactions of organic compounds using deoxofluor and DAST Synthesis 2002, 17, 2561 - 2578
42. Kirk, K. L. Fluorination in Medicinal Chemistry: Methods, Strategies, and Recent Developments Org. Process Res. Dev. 2008, 12 (2) 305 - 321
43. Al-Maharik, N.; O'Hagan, D. Organofluorine chemistry. Deoxyfluorination reagents for C-F bond synthesis Aldrichimica Acta 2011, 44 (3) 65 - 75
44. Messina, P. A.; Mange, K. C.; Middleton, W. J. Aminosulfur trifluorides: relative thermal stability J. Fluorine Chem. 1989, 42 (1) 137 - 143
45. Middleton, W. J. Explosive hazards with DAST [diethylaminosulfur trifluoride] Chem. Eng. News 1979, 57 (21) 43
46. L'Heureux, A.; Beaulieu, F.; Bennett, C.; Bill, D. R.; Clayton, S.; La Flamme, F.; Mirmehrabi, M.; Tadayon, S.; Tovell, D.; Couturier, M. Aminodifluorosulfinium Salts: Selective Fluorination Reagents with Enhanced Thermal Stability and Ease of Handling J. Org. Chem. 2010, 75 (10) 3401 - 3411
47. Devos, A.; Remion, J.; Frisque-Hesbain, A. M.; Colens, A.; Ghosez, L. Synthesis of acyl halides under very mild conditions J. Chem. Soc., Chem. Commun. 1979, 24, 1180 - 1181
48. Ghosez, L. α-Chloroenamines. New reagents for organic synthesis Angew. Chem., Int. Ed. Engl. 1972, 11 (9) 852 - 853
49. Burgess, E. M.; Penton, H. R., Jr.; Taylor, E. A. Thermal reactions of alkyl N -carbomethoxysulfamate esters J. Org. Chem. 1973, 38 (1) 26 - 31
50. Kalvass, J. C.; Maurer, T. S. Use of plasma and brain unbound fractions to assess the extend of brain distribution of 34 drugs: comparison of unbound concentration ratios to in vivo P-glycoprotein efflux ratios Biopharm. Drug Dispos. 2002, 23 (8) 327
51. Kutchinsky, J.; Friis, S.; Asmild, M.; Taboryski, R.; Pedersen, S.; Vestergaard, R. K.; Jacobsen, R. B.; Krzywkowski, K.; Schroder, R. L.; Ljungstrom, T.; Helix, N.; Sorensen, C. B.; Bech, M.; Willumsen, N. J. Characterization of Potassium Channel Modulators with QPatch Automated Patch-Clamp Technology: System Characteristics and Performance Assay Drug Dev. Technol. 2003, 1 (5) 685 - 693
52. Bridges, K. G.; Chopra, R.; Lin, L.; Svenson, K.; Tam, A.; Jin, G.; Cowling, R.; Lovering, F.; Akopian, T. N.; DiBlasio-Smith, E.; Annis-Freeman, B.; Marvell, T. H.; LaVallie, E. R.; Zollner, R. S.; Bard, J.; Somers, W. S.; Stahl, M. L.; Kriz, R. W. A novel approach to identifying β-secretase inhibitors: Bis-statine peptide mimetics discovered using structure and spot synthesis Peptides (N. Y., N Y, U. S. A.) 2006, 27 (7) 1877 - 1885
53. Otwinowski, Z.; Minor, W. Processing of x-ray diffraction data collected in oscillation mode Methods Enzymol. 1997, 276, 307 - 326 Macromolecular Crystallography, Part A
54. 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
55. Emsley, P.; Cowtan, K. Coot: model-building tools for molecular graphics Acta Crystallogr., Sect. D: Biol. Crystallogr. 2004, D60 (12, Pt. 1) 2126 - 2132
56. Bricogne, G.; Blanc, E.; Brandl, M.; Flensburg, C.; Keller, P.; Paciorek, W.; Roversi, P.; Smart, O. S.; Vonrhein, C.; Womack, T. O. BUSTER, 2.8.0; Global Phasing Ltd.: Cambridge, UK, 2009.
57. Wang, A.; Stout, C. D.; Zhang, Q.; Johnson, E. F. Contributions of Ionic Interactions and Protein Dynamics to Cytochrome P450 2D6 (CYP2D6)Substrate and Inhibitor Binding J. Biol. Chem. 2015, 290, 5092 - 5104
58. Kabsch, W. XDS Acta Crystallogr. D Biol. Crystallogr. 2010, 66 (Pt 2) 125 - 132
59. Adams, P. D.; Afonine, P. V.; Bunkoczi, G.; Chen, V. B.; Davis, I. W.; Echols, N.; Headd, J. J.; Hung, L.-W.; Kapral, G. J.; Grosse-Kunstleve, R. W.; McCoy, A. J.; Moriarty, N. W.; Oeffner, R.; Read, R. J.; Richardson, D. C.; Richardson, J. S.; Terwilliger, T. C.; Zwart, P. H. PHENIX: a comprehensive Python-based system for macromolecular structure solution Acta Crystallogr., Sect. D: Biol. Crystallogr. 2010, 66 (Pt 2) 213 - 221