Discovery of highly potent, selective, and brain-penetrable leucine-rich repeat kinase 2 (LRRK2) small molecule inhibitors

Journal of Medicinal Chemistry

Volumn 55, Issue 22, 2012, Pages 9416-9433

  Estrada, Anthony A ^a   Liu, Xingrong ^a   Baker Glenn, Charles ^b   Beresford, Alan ^b   Burdick, Daniel J ^a   Chambers, Mark ^b   Chan, Bryan K ^a   Chen, Huifen ^a   Ding, Xiao ^a   Dipasquale, Antonio G ^c   Dominguez, Sara L ^a   Dotson, Jennafer ^a   Drummond, Jason ^a   Flagella, Michael ^a   Flynn, Sean ^b   Fuji, Reina ^a   Gill, Andrew ^b   Gunzner Toste, Janet ^a   Harris, Seth F ^a   Heffron, Timothy P ^a   Kleinheinz, Tracy ^a   Lee, Donna W ^a   Le Pichon, Claire E ^a   Lyssikatos, Joseph P ^a   Medhurst, Andrew D ^b   Moffat, John G ^a   Mukund, Susmith ^a   Nash, Kevin ^b   Scearce Levie, Kimberly ^a   Sheng, Zejuan ^a   Shore, Daniel G ^a   Tran, Thuy ^a   Trivedi, Naimisha ^b   Wang, Shumei ^a   Zhang, Shuo ^a   Zhang, Xiaolin ^a   Zhao, Guiling ^a   Zhu, Haitao ^a   Sweeney, Zachary K ^a,d   more..

^a GENENTECH INC   (United States)

^b BioFocus ^*  (United Kingdom)

^c UNIVERSITY OF CALIFORNIA   (United States)

^d NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

( 4 ( 4 (CYCLOPROPYLAMONO) 5 (TRIFLUOROMETHYL)PYRIMIDIN 2 YLAMINO) 2 FLUORO 5 METHOXYPHENYL)(MORPHOLINO)METHANONE; ( 4 ( 4 (ETHYLAMINOO) 5 (TRIFLUOROMETHYL)PYRIMIDIN 2 YLAMINO) 2 FLUORO 5 METHOXYPHENYL)(MORPHOLINO)METHANONE; GNE 7915; LEUCINE RICH REPEAT KINASE 2; LEUCINE RICH REPEAT KINASE 2 INHIBITOR; LIGAND; PROTEIN KINASE INHIBITOR; PROTEIN SERINE THREONINE KINASE INHIBITOR; PYRIMIDINE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; AREA UNDER THE CURVE; ARTICLE; BRAIN; CONTROLLED STUDY; CRYSTAL STRUCTURE; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG DESIGN; DRUG DISTRIBUTION; DRUG METABOLISM; DRUG PENETRATION; DRUG POTENCY; DRUG SELECTIVITY; DRUG SOLUBILITY; DRUG STABILITY; HIGH THROUGHPUT SCREENING; HUMAN; HUMAN CELL; IC 50; IN VITRO STUDY; IN VIVO STUDY; MAXIMUM PLASMA CONCENTRATION; MOLECULAR MODEL; NONHUMAN; PHARMACODYNAMICS; PROCESS OPTIMIZATION; PROTEIN STABILITY; RAT; RISK ASSESSMENT; RODENT; STRUCTURE ACTIVITY RELATION;

ANIMALS; BRAIN; DRUG DESIGN; HUMANS; MACACA FASCICULARIS; MICE; MICE, TRANSGENIC; MODELS, MOLECULAR; MORPHOLINES; PARKINSON DISEASE; PROTEIN KINASE INHIBITORS; PROTEIN-SERINE-THREONINE KINASES; PYRIMIDINES; RATS; SMALL MOLECULE LIBRARIES; TISSUE DISTRIBUTION;

EID: 84870051317     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm301020q     Document Type: Article

References (68)

1. Lees, A. J.; Hardy, J.; Revesz, T. Parkinson's disease Lancet 2009, 373, 2055-2066
2. Erratum in Lancet 2009, 374, 684.
3. Zimprich, A.; Biskup, S.; Leitner, P.; Lichtner, P.; Farrer, M.; Lincoln, S.; Kachergus, J.; Hulihan, M.; Uitti, R. J.; Calne, D. B.; Stoessl, A. J.; Pfeiffer, R. F.; Patenge, N.; Carbajal, I. C.; Vieregge, P.; Asmus, F.; Muller-Myhsok, B.; Dickson, D. W.; Meitinger, T.; Strom, T. M.; Wszolek, Z. K.; Gasser, T. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology Neuron 2004, 44, 601-607
4. Paisan-Ruiz, C.; Jain, S.; Evans, E. W.; Gilks, W. P.; Simon, J.; van der Brug, M.; Lopez de Munain, A.; Aparicio, S.; Gil, A. M.; Khan, N.; Johnson, J.; Martinez, J. R.; Nicholl, D.; Carrera, I. M.; Pena, A. S.; de Silva, R.; Lees, A.; Marti-Masso, J. F.; Perez-Tur, J.; Wood, N. W.; Singleton, A. B. Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease Neuron 2004, 44, 595-600
5. Mata, I. F.; Wedemeyer, W. J.; Farrer, M. J.; Taylor, J. P.; Gallo, K. A. LRRK2 in Parkinson's disease: protein domains and functional insights Trends Neurosci. 2006, 29, 286-293
6. Greggio, E.; Cookson, M. R. Leucine-rich repeat kinase 2 mutations and Parkinson's disease: three questions ASN Neuro 2009, 1, e00002
7. Gandhi, P. N.; Chen, S. G.; Wilson-Delfosse, A. L. Leucine-rich repeat kinase 2 (LRRK2): a key player in the pathogenesis of Parkinson's disease J. Neurosci. Res. 2009, 87, 1283-1295
8. Dachsel, J. C.; Farrer, M. J. LRRK2 and Parkinson disease Arch. Neurol. 2010, 67, 542-547
9. Satake, W.; Nakabayashi, Y.; Mizuta, I.; Hirota, Y.; Ito, C.; Kubo, M.; Kawaguchi, T.; Tsunoda, T.; Watanabe, M.; Takeda, A.; Tomiyama, H.; Nakashima, K.; Hasegawa, K.; Obata, F.; Yoshikawa, T.; Kawakami, H.; Sakoda, S.; Yamamoto, M.; Hattori, N.; Murata, M.; Nakamura, Y.; Toda, T. Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease Nat. Genet. 2009, 41, 1303-1307
10. Simón-Sánchez, J.; Schulte, C.; Bras, J. M.; Sharma, M.; Gibbs, J. R.; Berg, D.; Paisan-Ruiz, C.; Lichtner, P.; Scholz, S. W.; Hernandez, D. G.; Krüger, R.; Federoff, M.; Klein, C.; Goate, A.; Perlmutter, J.; Bonin, M.; Nalls, M. A.; Illig, T.; Gieger, C.; Houlden, H.; Steffens, M.; Okun, M. S.; Racette, B. A.; Cookson, M. R.; Foote, K. D.; Fernandez, H. H.; Traynor, B. J.; Schreiber, S.; Arepalli, S.; Zonozi, R.; Gwinn, K.; van der Brug, M.; Lopez, G.; Chanock, S. J.; Schatzkin, A.; Park, Y.; Hollenbeck, A.; Gao, J.; Huang, X.; Wood, N. W.; Lorenz, D.; Deuschl, G.; Chen, H.; Riess, O.; Hardy, J. A.; Singleton, A. B.; Gasser, T. Genome-wide association study reveals genetic risk underlying Parkinson's disease Nat. Genet. 2009, 41, 1308-1312
11. West, A. B.; Moore, D. J.; Biskup, S.; Bugayenko, A.; Smith, W. W.; Ross, C. A.; Dawson, V. L.; Dawson, T. M. Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 16842-16847
12. Greggio, E.; Jain, S.; Kingsbury, A.; Bandopadhyay, R.; Lewis, P.; Kaganovich, A.; van der Brug, M. P.; Beilina, A.; Blackinton, J.; Thomas, K. J.; Ahmad, R.; Miller, D. W.; Kesavapany, S.; Singleton, A.; Lees, A.; Harvey, R. J.; Harvey, K.; Cookson, M. R. Kinase activity is required for the toxic effects of mutant LRRK2/dardarin Neurobiol. Dis. 2006, 23, 329-341
13. Cookson, M. R. The role of leucine-rich repeat kinase 2 (LRRK2) in Parkinson's disease Nat. Rev. Neurosci. 2010, 11, 791-797
14. Rudenko, I. N.; Chia, R.; Cookson, M. R. Is inhibition of kinase activity the only therapeutic strategy for LRRK2-associated Parkinson's disease? BMC Med. 2012, 10, 20-27
15. Liu, Z.; Hamamichi, S.; Lee, B. D.; Yang, D.; Ray, A.; Caldwell, G. A.; Caldwell, K. A.; Dawson, T. M.; Smith, W. W.; Dawson, V. L. Inhibitors of LRRK2 kinase attenuate neurodegeneration and Parkinson-like phenotypes in Caenorhabditis elegans and Drosophila Parkinson's disease models Hum. Mol. Genet. 2011, 20, 3933-3942
16. Lee, B. D.; Shin, J.-H.; VanKampen, J.; Petrucelli, L.; West, A. B.; Ko, H. S.; Lee, Y.-I.; Maguire-Zeiss, K. A.; Bowers, W. J.; Federoff, H. J.; Dawson, V. L.; Dawson, T. M. Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson's disease Nat. Med. 2010, 16, 998-1000
17. For a recent review on LRRK2 small molecule kinase inhibitors, see the following: Kramer, T.; Lo Monte, F.; Göring, S.; Amombo, G. M. O.; Schmidt, B. Small molecule kinase inhibitors for LRRK2 and their application to Parkinson's disease models ACS Chem. Neurosci. 2012, 3, 151-160
18. Lee, B. D.; Dawson, V. L.; Dawson, T. M. Leucine-rich repeat kinase 2 (LRRK2) as a potential therapeutic target in Parkinson's disease Trends Pharmacol. Sci. 2012, 33, 365-373
19. Deng, X.; Dzamko, N.; Prescott, A.; Davies, P.; Liu, Q.; Yang, Q.; Lee, J.-D.; Patricelli, M. P.; Nomanbhoy, T. K.; Alessi, D. R.; Gray, N. S. Characterization of a selective inhibitor of the Parkinson's disease kinase LRRK2 Nat. Chem. Biol. 2011, 7, 203-205
20. Ramsden, N.; Perrin, J.; Ren., Z.; Lee, B. D.; Zinn, N.; Dawson, V. L.; Tam, D.; Bova, M.; Lang, M.; Drewes, G.; Bantscheff, M.; Bard, F.; Dawson, T. M.; Hopf, C. Chemoproteomics-based design of potent LRRK2-selective lead compounds that attenuate Parkinson's disease-related toxicity in human neurons ACS Chem. Biol. 2011, 6, 1021-1028
21. Nichols, P. L.; Eatherton, A. J.; Bamborough, P.; Jandu, K. S.; Philps, O. J.; Andreotti, D. Novel Compounds. WO 2011/038572 A1, 2011.
22. Lewis, P. A.; Manzoni, C. LRRK2 and human disease: a complicated question or a question of complexes? Sci. Signaling 2012, 5, pe2
23. Drolet, R. E.; Sanders, J. M.; Kern, J. T. Leucine-rich repeat kinase 2 (LRRK2) cellular biology: a review of recent advances in identifying physiological substrates and cellular functions J. Neurogenet. 2011, 25, 140-151
24. Zhang, J.; Deng, X.; Choi, H. G.; Alessi, D. R.; Gray, N. S. Characterization of TAE684 as a potent LRRK2 kinase inhibitor Bioorg. Med. Chem. Lett. 2012, 22, 1864-1869
25. Sheng, Z.; Zhang, S.; Bustos, D.; Kleinheinz, T.; Le Pichon, C. E.; Dominguez, S. L.; Solanoy, H. O.; Drummond, J.; Zhang, X.; Ding, X.; Cai, F.; Song, Q.; Li, X.; Yue, Z.; van der Brug, M. P.; Burdick, D. J.; Gunzner-Toste, J.; Chen, H.; Liu, X.; Estrada, A. A.; Sweeney, Z. K.; Scearce-Levie, K.; Moffat, J. G.; Kirkpatrick, D. S.; Zhu, H. Ser1292 autophosphorylation is a biomarker of LRRK2 kinase activity and mediates cellular effects of PD mutations. Sci. Transl. Med. 2012, in press.
26. Chen, H.; Chan, B. K.; Drummond, J.; Estrada, A. A.; Gunzner-Toste, J.; Liu, X.; Liu, Y.; Moffat, J. G.; Shore, D.; Sweeney, Z. K.; Tran, T.; Wang, S.; Zhao, G.; Zhu, H.; Burdick, D. J. Discovery of selective LRRK2 inhibitors guided by computational analysis and molecular modeling J. Med. Chem. 2012, 55, 5536-5545
27. Li, X.; Patel, J. C.; Wang, J.; Avshalumov, M. V.; Nicholson, C.; Buxbaum, J. D.; Elder, G. A.; Rice, M. E.; Yue, Z. Enhanced striatal dopamine transmission and motor performance with LRRK2 overexpression in mice is eliminated by familial Parkinson's disease mutation G2019S J. Neurosci. 2010, 30, 1788-1797
28. Hu, X.; Hu, Y.; Vogt, M.; Stumpfe, D.; Bajorath, J. MMP-Cliffs: systematic identification of activity cliffs on the basis of matched molecular pairs J. Chem. Inf. Model. 2012, 52, 1138-1145
29. Muller, K. The power of MMPA and a teaching lesson in medicinal chemistry J. Med. Chem. 2012, 55, 1815-1816
30. Stumpfe, D.; Bajorath, J. Exploring activity cliffs in medicinal chemistry J. Med. Chem. 2012, 55, 2932-2942
31. Griffen, E.; Leach, A. G.; Robb, G. R.; Warner, D. J. Matched molecular pairs as a medicinal chemistry tool J. Med. Chem. 2011, 54, 7739-7750
32. Hu, Y.; Bajorath, J. Chemical transformations that yield compounds with distinct activity profiles ACS Med. Chem. Lett. 2011, 2, 523-527
33. Milletti, F.; Hermann, J. C. Targeted kinase selectivity from kinase profiling data ACS Med. Chem. Lett. 2012, 3, 383-386
34. Galkin, A. V.; Melnick, J. S.; Kim, S.; Hood, T. L.; Li, N.; Li, L.; Xia, G.; Steensma, R.; Chopiuk, G.; Jiang, J.; Wan, Y.; Ding, P.; Liu, Y.; Sun, F.; Schultz, P. G.; Gray, N. S.; Warmuth, M. Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 270-275
35. Erratum in Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 2025.
36. Anderson, D. R.; Meyers, M. J.; Vernier, W. F.; Mahoney, M. W.; Kurumbail, R. G.; Caspers, N.; Poda, G. I.; Schindler, J. F.; Reitz, D. B.; Mourey, R. J. Pyrrolopyridine inhibitors of mitogen-activated protein kinase activated protein kinase 2 (MK-2) J. Med. Chem. 2007, 50, 2647-2654
37. Baker-Glenn, C.; Burdick, D. J.; Chambers, M.; Chan, B. K.; Chen, H.; Estrada, A.; Gunzner, J. L.; Shore, D.; Sweeney, Z. K.; Wang, S.; Zhao, G. Aminopyrimidine derivatives as LRRK2 modulators and their preparation and use for the treatment of Parkinson's disease. WO2011151360A1, 2011.
38. Choi, H. G.; Zhang, J.; Deng, X.; Hatcher, J. M.; Patricelli, M. P.; Zhao, Z.; Alessi, D. R.; Gray, N. S. Brain penetrant LRRK2 inhibitor ACS Med. Chem. Lett. 2012, 3, 658-662
39. Wager, T. T.; Hou, X.; Verhoest, P. R.; Villalobos, A. Moving beyond the rules: the development of a central nervous system multiparameter optimization (CNS MPO) approach to enable alignment of druglike properties ACS Chem. Neurosci. 2010, 1, 435-449
40. Leeson, P. D.; Springthorpe, B. The influence of drug-like concepts on decision-making in medicinal chemistry Nat. Rev. Drug Discovery 2007, 6, 881-890
41. Keseru, G. M.; Makara, G. M. The influence of lead discovery strategies on the properties of drug candidates Nat. Rev. Drug Discovery 2009, 8, 203-212
42. Tarcsay, A.; Nyíri, K.; Keseru, G. M. Impact of lipophilic efficiency on compound quality J. Med. Chem. 2012, 55, 1252-1260
43. For impact on CNS drugs and candidates, see the following: 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, 420-434
44. Liu, X.; Ding, X.; Deshmukh, G.; Liederer, B. M.; Hop, C. E. C. A. Use of cassette dosing approach to assess brain penetration in drug discovery Drug Metab. Dispos. 2012, 40, 963-969
45. Hennig, L.; Ayala-Leon, K.; Angulo-Cornejo, J.; Richter, R.; Beyer, L. Fluorine hydrogen short contacts and hydrogen bonds in substituted benzamides J. Fluorine Chem. 2009, 130, 453-460
46. Fritz, H.; Winkler, T. Weitreichende kopplung zwischen protonen und fluor in 2-fluorbenzamiden Helv. Chim. Acta 1974, 57, 836-839
47. Hitchcock, S. A. Structural modifications that alter the P-glycoprotein efflux properties of a compound J. Med. Chem. 2012, 55, 4877-4895
48. 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
49. Ishikawa, M.; Hashimoto, Y. Improvement in aqueous solubility in small molecule drug discovery programs by disruption of molecular planarity and symmetry J. Med. Chem. 2011, 54, 1539-1554
50. Liu, X.; Smith, B. J.; Chen, C.; Callegari, E.; Becker, S. L.; Chen, X.; Cianfronga, J.; Doran, A. C.; Doran, S. D.; Gibbs, J. P.; Hosea, N.; Liu, J.; Nelson, F. R.; Szewc, M. A.; Van Deusen, J. Evaluation of cerebrospinal fluid concentration and plasma free concentration as a surrogate measurement for brain free concentration Drug Metab. Dispos. 2006, 34, 1443-1447
51. Lin, J. H. CSF as a surrogate for assessing CNS exposure: an industrial perspective Curr. Drug Metab. 2008, 9, 46-59
52. Invitrogen Lanthascreen Eu kinase binding assay kit for TTK.
53. Kwiatkowski, N.; Jelluma, N.; Filippakopoulos, P.; Soundararajan, M.; Manak, M. S.; Kwon, M.; Choi, H. G.; Sim, T.; Deveraux, Q. L.; Rottmann, S.; Pellman, D.; Shah, J. V.; Kops, G. J. P.; Knapp, S.; Gray, N. S. Small-molecule kinase inhibitors provide insight into Mps1 cell cycle function Nat. Chem. Biol. 2010, 6, 359-368
54. Olaharski, A. J.; Gonzaludo, N.; Bitter, H.; Goldstein, D.; Kirchner, S.; Uppal, H.; Kolaja, K. Identification of a kinase profile that predicts chromosome damage induced by small molecule kinase inhibitors PLoS Comput. Biol. 2009, 5, e1000446
55. Lan, W.; Cleveland, D. W. A chemical tool box defines mitotic and interphase roles for Mps1 kinase J. Cell Biol. 2010, 190, 21-24
56. Wilberg, K. B. The deuterium isotope effect Chem. Rev. 1955, 55, 713
57. Hitchcock, S. A.; Pennington, L. D. Structure-brain exposure relationships J. Med. Chem. 2006, 49, 7559-7583
58. Fabian, M. A.; Biggs, W. H.; Treiber, D. K.; Atteridge, C. E.; Azimioara, M. D.; Benedetti, M. G.; Carter, T. A.; Ciceri, P.; Edeen, P. T.; Floyd, M.; Ford, J. M.; Galvin, M.; Gerlach, J. L.; Grotzfeld, R. M.; Herrgard, S.; Insko, D. E.; Insko, M. A.; Lai, A. G.; Lélias, J.-M.; Mehta, S. A.; Milanov, Z. V.; Velasco, A. M.; Wodicka, L. M.; Patel, H. K.; Zarrinkar, P. P.; Lockhart, D. J. A small molecule-kinase interaction map for clinical kinase inhibitors Nat. Biotechnol. 2005, 23, 329-336
59. Porter, R. H.; Benwell, K. R.; Lamb, H.; Malcolm, C. S.; Allen, N. H.; Revell, D. F.; Adams, D. R.; Sheardown, M. J. Functional characterization of agonists at recombinant human 5-HT2A, 5-HT2B and 5-HT2C receptors in CHO-K1 cells Br. J. Pharmacol. 1999, 128, 13-20
60. Zhou, S.-F.; Wang, B.; Yang, L.-P.; Liu, J.-P. Structure, function, regulation and polymorphism and the clinical significance of human cytochrome P450 1A2 Drug Metab. Rev. 2010, 42, 268-354
61. Zhou, S.-F.; Yang, L.-P.; Zhou, Z.-W.; Liu, Y.-H.; Chan, E. Insights into the substrate specificity, inhibitors, regulation, and polymorphisms and the clinical impact of human cytochrome P450 1A2 AAPS J. 2009, 11, 481-494
62. Akabane, T.; Tabata, K.; Kadono, K.; Sakuda, S.; Terashita, S.; Teramura, T. A comparison of pharmacokinetics between humans and monkeys Drug Metab. Dispos. 2010, 38, 308-316
63. Roller, S.; Cui, D.; Laspina, C.; Miller-Stein, C.; Rowe, J.; Wong, B; Prueksaritanont, T. Preclinical pharmacokinetics of MK-0974, an orally active calcitonin-gene related peptide (CGRP)-receptor antagonist, mechanism of dose dependency and species differences Xenobiotica 2009, 39, 33-45
64. MOE, version 2009.10; Chemical Computing Group Inc.: Montreal, Quebec, Canada.
65. Wang, J.; Cieplak, P.; Kollman, P. A. How well does a restrained electrostatic potential (RESP) model perform in calculating conformational energies of organic and biological molecules? J. Comput. Chem. 2000, 21, 1049
66. Bairoch, A.; Boeckmann, B.; Ferro, S.; Gasteiger, E. Swiss-Prot: juggling between evolution and stability Briefings Bioinf. 2004, 5, 39-55
67. Thompson, J. D.; Higgins, D. G.; Gibson, T. J. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position specific gap penalties and weight matrix choice Nucleic Acids Res. 1994, 22, 4673-4680
68. Maestro Suites, version 2009; Schrödinger, Inc.: New York, 2009.