Crystal structures, binding interactions, and ADME evaluation of brain penetrant N-substituted indazole-5-carboxamides as subnanomolar, selective monoamine oxidase B and dual MAO-A/B inhibitors

European Journal of Medicinal Chemistry

Volumn 127, Issue , 2017, Pages 470-492

  Tzvetkov, Nikolay T ^a   Stammler, Hans Georg ^b   Neumann, Beate ^b   Hristova, Silvia ^c   Antonov, Liudmil ^c   Gastreich, Marcus ^d  

^a NTZ Lab Ltd   (Bulgaria)

^b BIELEFELD UNIVERSITY   (Germany)

^c INSTITUTE OF ORGANIC CHEMISTRY   (Bulgaria)

^d BioSolveIT GmbH   (Germany)

Author keywords

ADME; Indazole 5 carboxamides; MAO inhibitors; Molecular modeling; Parkinson's disease; X ray

Indexed keywords

AMIDE; CARBONYL DERIVATIVE; INDAZOLE 5 CARBOXAMIDE DERIVATIVE; INDAZOLE DERIVATIVE; MOCLOBEMIDE; MONOAMINE OXIDASE INHIBITOR; N (3 CHLORO 4 FLUOROPHENYL) 1 METHYL 1H INDAZOLE 5 CARBOXAMIDE; N (3 CHLORO 4 FLUOROPHENYL) 2 METHYL 2H INDAZOLE 5 CARBOXAMIDE; N (3,4 DICHLOROPHENYL) 1 (2 METHOXYETHYL) 1H INDAZOLE 5 CARBOXAMIDE; N (3,4 DICHLOROPHENYL) 1 METHYL 1H INDAZOLE 5 CARBOXAMIDE; N (3,4 DICHLOROPHENYL) 2 METHYL 2H INDAZOLE 5 CARBOXAMIDE; N (3,4 DIFLUOROPHENYL) 1 METHYL 1H INDAZOLE 5 CARBOXAMIDE; N (3,4 DIFLUOROPHENYL) 2 METHYL 2H INDAZOLE 5 CARBOXAMIDE; NITROGEN DERIVATIVE; SAFINAMIDE; THEOPHYLLINE; UNCLASSIFIED DRUG; VERAPAMIL; AMINE OXIDASE (FLAVIN CONTAINING); PROTEIN BINDING; WATER;

ARTICLE; BLOOD BRAIN BARRIER; CONTROLLED STUDY; CRYSTAL STRUCTURE; DRUG ABSORPTION; DRUG BINDING; DRUG DISTRIBUTION; DRUG EXCRETION; DRUG INTERACTION; DRUG METABOLISM; DRUG POTENCY; DRUG SCREENING; HUMAN; HYDROGEN BOND; IC50; IN VITRO STUDY; INTESTINE MUCOSA PERMEABILITY; MOLECULAR DOCKING; MOLECULAR MODEL; NONHUMAN; PHARMACOPHORE; RAT; STOMACH PH; ANIMAL; BRAIN; CHEMISTRY; GASTROINTESTINAL TRACT; KINETICS; METABOLISM; PERMEABILITY; PROTEIN CONFORMATION; SOLUBILITY; SPECIES DIFFERENCE; STRUCTURE ACTIVITY RELATION; X RAY CRYSTALLOGRAPHY;

ANIMALS; BLOOD-BRAIN BARRIER; BRAIN; CRYSTALLOGRAPHY, X-RAY; GASTROINTESTINAL TRACT; HUMANS; INDAZOLES; KINETICS; MOLECULAR DOCKING SIMULATION; MONOAMINE OXIDASE; MONOAMINE OXIDASE INHIBITORS; PERMEABILITY; PROTEIN BINDING; PROTEIN CONFORMATION; RATS; SOLUBILITY; SPECIES SPECIFICITY; STRUCTURE-ACTIVITY RELATIONSHIP; WATER;

EID: 85009460303     PISSN: 02235234     EISSN: 17683254     Source Type: Journal    
DOI: 10.1016/j.ejmech.2017.01.011     Document Type: Article

References (74)

1. [1] Kakkar, A.K., Dahiya, N., Management of Parkinsons's disease: current and future pharmacology. Eur. J. Pharmacol. 750 (2015), 74–81.
2. [2] Samii, A., Nutt, J.G., Ransom, B.R., Parkinson's disease. Lancet 363 (2004), 1783–1793.
3. [3] Singer, C., Managing the patient with newly diagnosed Parkinson's disease. Clev. Clin. J. Med. 79:Suppl. 2 (2012), S3–S7.
4. [4] Zigmond, J.M., Smeyne, R.J., Exercise: is it a neuroprotective and if so, how does it work?. Parkinsonism Rel. Disord. 20:Suppl. 1 (2014), S123–S127.
5. [5] Dauer, W., Przedborski, S., Parkinson's disease: mechanism and models. Neuron 39 (2003), 889–909.
6. [6] Girault, J.-A., Greengard, P., The neurobiology of dopamine signaling. Arch. Neurol. 61 (2004), 641–644.
7. [7] Imai, Y., Lu, B., Mitochondrial dynamics and mitophagy in Parkinson's disease: disordered cellular power plant becomes a big deal in a major movement disorder. Curr. Opin. Neurobiol. 21 (2011), 935–941.
8. [8] Kondo, T., Mizuno, Y., Japanese Istradefylline Study Group, A long-term study of istradefylline safety and efficacy in patients with Parkinson's disease. Clin. Neuropharmcol 38 (2015), 41–46.
9. [9] Dunkel, P., Chai, C.L., Sperlágh, B., Huleatt, P.B., Mátyus, P., Clinical utility of neuroprotective agents in neurodegenerative disease: current status of drug development for Alzheimer's, Parkinson's and Huntington's diseases, and amyotrophic lateral sclerosis. Exp. Opin. Investig. Drugs 21 (2012), 1267–1308.
10. [10] Jankovic, J., Poewe, W., Therapies in Parkinson's disease. Curr. Opin. Neurol. 25 (2012), 433–447.
11. [11] Kurth, J.H., Kurth, M.C., Role of monoamine oxidase genetics in the etiology of Parkinson's disease. Lieberman, A., Olanow, C.W., Youdim, M.B.H., Tipton, K., (eds.) Monoamine Oxidase Inhibitors in Neurological Diseases, 1994, Marcel Dekker Inc., New York, 113–126.
12. [12] Whibley, A., Urquhart, J., Dore, J., Willatt, L., Parkin, G., Gaunt, L., Black, G., Donnai, D., Raymond, F.L., Deletion of MAOA and MAOB in a male patient causes severe developmental delay, intermittent hypotonia and stereotypical hand movements. Eur. J. Hum. Gen. 18 (2010), 1095–1099.
13. [13] Tong, J., Meyer, J.H., Furukawa, Y., Boileau, L., Chang, L.-J., Wilson, A.A., Houle, S., Kish, S.J., Distribution of monoamine oxidase proteins in human brain: implication for brain imaging studies. J. Cereb. Blood Flow. Metab. 33 (2013), 863–871.
14. [14] Shih, J.C., Chen, K., Ridd, M.J., Monoamine oxidase: from genes to behavior. Ann. Rev. Neurosci. 22 (1999), 197–217.
15. [15] Nicotra, A., Pierucci, F., Parvez, H., Senatori, O., Monoamine oxidase expression during development and aging. NeuroToxicology 25 (2004), 155–165.
16. [16] Youdim, M.B.H., Lavie, L., Selective MAO-A and MAO-B inhibitors, radical scavengers and nitric oxide synthase inhibitors in Parkinson's disease. Life Sci. 55 (1994), 2077–2082.
17. [17] Kennedy, B.P., Ziegler, M.G., Alford, M., Hansen, L.A., Thal, L.J., Masliah, E., Early and persistent alterations in prefrontal cortex MAO A and B in Alzheimer's disease. J. Neural Transm. 110 (2003), 789–801.
18. [18] Emilsson, L., Saetre, P., Balciuniene, J., Castensson, A., Cairns, N., Jazin, E.E., Increased monoamine oxidase messenger RNA expression levels in frontal cortex of Alzheimer's disease patients. Neurosci. Lett. 326 (2002), 56–60.
19. [19] Riederer, P., Lachenmayer, L., Laux, G., Clinical applications of MAO-inhibitors. Curr. Med. Chem. 11 (2004), 2033–2043.
20. [20] Lotufo-Neto, F., Trivedi, M., Thase, M.E., Meta-analysis of the reversible inhibitors of monoamine oxidase type A moclobemide and brofaromine for the treatment of depression. Neuropsychopharmacol 20 (1999), 226–247.
21. [21] Fowler, J.S., Logan, J., Volkow, N.D., Shumay, E., McCall-Perez, F., Jayne, M., Wang, G.-J., Alexoff, D.L., Apelskog-Torres, K., Hubbard, B., Carter, P., King, P., Fahn, S., Gilmor, M., Telang, F., Shea, C., Xu, Y., Muench, L., Evidence that formulations of the selective MAO-B inhibitor selegiline, which bypass first-pass metabolism, also inhibit MAO-A in the human brain. Neuropsychopharmacol 40 (2015), 650–657.
22. [22] Lakhan, S.E., From a Parkinson's disease expert: rasagiline and the future of therapy. Mol. Neurodegener. 2 (2007), 1–3.
23. [23] Kumar, B., Sheetal, Mantha, A.K., Kumar, V., Recent developments on the structure-activity relationship studies of MAO inhibitors and their role in different neurological disorders. RSC Adv. 6 (2016), 42660–42683.
24. [24] Deeks, E.D., Safinamide: first global approval. Drugs 75 (2015), 705–711.
25. [25] Cattaneo, C., La Ferla, R., Bonizzoni, E., Sardina, M., Long-term effects of safinamide on dyskinesia in mid-to late-stage Parkinson's disease: a post-hoc analysis. J. Parkinson's Dis. 5 (2015), 475–481.
26. [26] Fabbri, M., Rosa, M.M., Abreu, D., Ferreira, J.J., Clinical pharmacology review of safinamide for the treatment of Parkinson's disease. Neurodegener. Dis. Manag. 5 (2015), 481–496.
27. [27] Carradori, S., Silvestri, R., New frontiers in selective human MAO-B inhibitors. J. Med. Chem. 58 (2015), 6717–6732.
28. [28] Joubert, J.J., Petzer, J.P., Prins, L.H.A., Repsold, B.P., Malan, S.F., Multifunctional enzyme inhibition for neuroprotection – a focus on MAO, NOS, and AChE inhibitors. Atta-ur-Rahman, Choudhary, M.I., (eds.) Drug Design and Discovery in Alzheimer's Disease, 2015, Elsevier Science Publishing Company Inc., Amsterdam, 291–365.
29. [29] Youdim, M.B.H., Kupershmidt, L., Amit, T., Weinreb, O., Promises of novel multi-target neuroprotective and neurorestorative drugs for Parkinson's disease. Park. Relat. Disord. 20S1 (2014), S132–S136.
30. [30] Tzvetkov, N.T., Hinz, S., Küppers, P., Gastreich, M., Müller, C.E., Indazole- and indole-5-carboxamides: selective and reversible monoamine oxidase B inhibitors with subnanomolar potency. J. Med. Chem. 57 (2014), 6679–6703.
31. [31] Tzvetkov, N.T., Substituted Indazole or Indole Derivatives as in Vitro MAO-b Inhibitors. 2014 WO2014/107771.
32. [32] M. Gastreich, N.T. Tzvetkov, Visual Rationalizing of Activity against Parkinson's and Alzheimer's Disease: Reversible MAO-b Inhibitors with Subnanomolar Potency, FMC, Antwerp, Belgium, September 14-16, 2015, P026.
33. [33] Prins, L.H.A., Petzer, J.P., Malan, S.F., Inhibition of monoamine oxidase by indole and benzofuran derivatives. Eur. J. Med. Chem. 45 (2010), 4458–4466.
34. [34] Tzvetkov, N.T., Neumann, B., Stammler, H.-G., Antonov, L., A simple approach to multifunctionalized N1-alkylated 7-amino-6-azaoxindole derivatives using there in situ stabilized tautomer form. Tetrahedron 72 (2016), 6455–6466.
35. [35] Holt, A., Sharman, D.F., Baker, G.B., Palcie, M.M., A continuous spectrophotometric assay for monoamine oxidase and related enzymes in tissue homogenates. Anal. Biochem. 244 (1997), 384–392.
36. [36] Mohanty, J.G., Jaffe, J.S., Schulman, E.S., Raible, D.G., A highly sensitive fluorescent micro-assay of H2O2release from activated human leukocytes using a dihydroxyphenoxazine derivative. J. Immunol. Methods 202 (1997), 133–141.
37. [37] Matos, M.J., Rodríduez-Enrí, F., Vilar, S., Santana, L., Uriarte, E., Hripcsak, G., Estrada, M., Rodríguez-Franco, M.I., Viña, D., Potent and selective MAO-B inhibitors activity: amino- versus nitro-3-arylcoumarin derivatives. Bioorg. Med. Chem. Lett. 25 (2015), 642–648.
38. [38] Binda, C., Hubálek, F., Min, L., Herzig, Y., Sterling, J., Salvati, P., Edmondson, D.E., Mattevi, A., A crystal structure of monoamine oxidase B in complex with four inhibitors of the N-propargylaminoindan class. J. Med. Chem. 47 (2004), 1767–1774.
39. [39] Tzvetkov, N.T., Pajeva, I.K., Binding and interactions of a novel potent indole-5-carboxamide MAO-B inhibitor. Compt. Rend. Acad. Bulg. Sci. 67 (2014), 937–942.
40. [40] Son, S.Y., Ma, J., Kondou, Y., Yoshimura, M., Yamashita, E., Tsukihara, T., Structure of human monoamine oxidase A at 2.2 Å resolution: the control of opening the entry for subtsrates/inhibitors. Proc. Natl. Acad. Sci. U.S.A. 105 (2008), 5739–5744.
41. [41] Binda, C., Wang, J., Pisani, L., Caccia, C., Carotti, A., Salvati, P., Edmondson, D.E., Mattevi, A., Structures of monoamine oxidase B complexes with selective non-covalent inhibitors: safinamide and coumarin analogs. J. Med. Chem. 50 (2007), 5848–5852.
42. [42] LeadIT v.2.1.9, BioSolveIT GmbH, Sankt Augustin, Germany. 2016 http://www.biosolveit.de.
43. [43] SeeSAR v.5.4, BioSolveIT GmbH, Sankt Augustin, Germany. 2016 http://www.biosolveit.de.
44. [44] Schneider, N., Lange, G., Hindle, S., Klein, R., Rarey, M., A consistent description of HYdrogen bond and DEhydratation energies in protein-ligand complexes: methods behind the HYDE scoring function. J. Comput.-Aided Mol. Des. 27 (2013), 15–29.
45. [45] These docking pose graphics were generated with the UCSF Chimera package v.1.10.2. Chimera is developed by the resource for biocomputing, visualization, and informatics at the University of California, san Francisco (supported by NIGMS P41–GM103311).
46. [46] Ruiz, F.X., Cousido-Siah, A., Porté, S., Dominguez, M., Crespo, I., Rechlin, C., Mitschler, A., de Lera, A.R., Martin, M.J., de la Fuente, J.À., Klebe, G., Parés, X., Farrés, J., Podjarny, A., Structural determination of the selectivity of 3-benzyluracil-1-acetic acids towards human enzymes aldose reductase and AKR1B10. ChemMedChem 10 (2015), 1989–2003.
47. [47] Klebe, G., Applying thermodynamic profiling in lead finding and optimization. Nat. Rev. Drug Discov. 14 (2015), 95–110.
48. [48] Betz, M., Wulsdorf, T., Krimmer, S.G., Klebe, G., Impact of surface water layers on protein–ligand binding: how well are experimental data reproduced by molecular dynamics simulations in a thermilysin test case. J. Chem. Inf. Model 56 (2016), 223–233.
49. [49] Cheng, Y.C., Prusoff, W.H., Relationships between the inhibition constant (Ki) and the concentration of inhibitor which causes 50% inhibition (IC50) of an enzymatic reaction. Biochem. Pharmacol. 22 (1973), 3099–3108.
50. [50] Reis, J., Cagide, F., Chavarria, D., Silva, T., Fernandes, C., Gaspar, A., Uriarte, E., Remião, F., Alcaro, S., Ortuso, F., Borges, F., Discovery of new chemical entities for old targets: insights on the lead optimization of chromone-based monoamine oxidase B (MAO-B) inhibitors. J. Med. Chem. 59 (2016), 5879–5893.
51. [51] Kawauchi, S., Antonov, L., Okuno, Y., Prediction of the color of dyes by using time-dependent density functional theory. Bulg. Chem. Comm. 46 (2014), 228–237.
52. [52] Clark, D.E., Rapid calculation of polar molecular surface area and its application to the prediction of transport phenomena. I. Prediction of intestinal absorption. J. Pharm. Sci. 88 (1999), 807–814.
53. [53] Vilar, S., Chakrabarti, M., Costanzi, S., Prediction of passive blood-brain partitioning: Straightforward and effective classification models based on in silico derived physicochemical descriptors. J. Mol. Graph. Model 28 (2010), 899–903.
54. [54] Freeman-Cook, K.D., Lipophilic efficiency: the most important efficiency metric in medicinal chemistry. Future Sci. 5 (2013), 113–115.
55. [55] Abad-Zapatero, C., Ligand efficiency indices for effective drug discovery, Expert Opin. Durg Discov. 2 (2007), 469–488.
56. [56] Wager, T.T., Hou, X., Verhoest, P.R., Villalobos, A., Moving beyond rules: the development of a central nervous system multiparameter optimization (CNS MPO) approach to enhance alignment of drug-like properties. ACS Chem. Neurosci. 1 (2010), 435–449.
57. [57] Hitchcock, S.A., Pennington, L.D., Structure-brain exposure relationships. J. Med. Chem. 49 (2006), 7559–7583.
58. [58] Johnson, T.W., Dress, K.R., Edwards, M., Using the Golden Triangle to optimize clearance and oral absorption. Bioorg. Med. Chem. Lett. 19 (2009), 5560–5564.
59. [59] Alsenz, J., Kansy, M., High throughput solubility measurement in drug discovery and development. Adv. Drug Deliv. Rev. 59 (2007), 546–567.
60. [60] Di, L., Kerns, E.H., Fan, K., McConnell, O.J., Carter, G.T., High throughput artificial membrane permeability assay for blood-brain barrier. Eur. J. Med. Chem. 38 (2003), 223–232.
61. [61] Avdeef, A., Permeability – PAMPA. Avdeef, A., (eds.) Absorption and Drug Development. Solubility, Permeability and Charge State, 2012, John Wiley & Sons, Inc., Hoboken, New Jersey, 319–498.
62. [62] Bujard, A., Sol, M., Carrupt, P.-A., Martel, S., Predicting both passive intestinal absorption and the dissociation constant toward albumin using the PAMPA technique. Eur. J. Pharm. Sci. 63 (2014), 36–44.
63. [63] Sinko, B., Garrigues, T.M., Balogh, G.T., Nagy, Z.K., Tsinman, O., Avdeef, A., Takacs-Novak, K., Skin-PAMPA: a new method for fast prediction of skin penetration. Eur. J. Pharm. Sci. 45 (2012), 698–707.
64. [64] Avdeef, A., Physicochemical profiling (solubility, permeability and charge state). Curr. Top. Med. Chem. 1 (2001), 277–351.
65. [65] Larregieu, C.A., Benet, L.Z., Distinguishing between the permeability relationships with absorption and metabolism to improve BCS and BDDCS predictions in early drug discovery. Mol. Pharm. 11 (2014), 1335–1344.
66. [66] Sheldrick, G.M., A short history of SHELX. Acta Crystallogr. A64 (2008), 112–122.
67. [67] Dolomanov, O.V., Bourhis, L.J., Gildea, R.J., Howard, J.A.K., Puschmann, H., OLEX2: a complete structure solution, refinement and analysis program. J. Appl. Crystallogr. 42 (2009), 339–341.
68. [68] Farrugia, L.J., WinGX and ORTEP for windows: an update. J. Appl. Crystallogr. 45 (2012), 849–854.
69. [69] Rarey, M., Kramer, B., Lengauer, T., Klebe, G., A fast flexible docking method using an incremental construction algorithm. J. Mol. Biol. 261 (1996), 470–489.
70. [70] Lemmen, C., Lengauer, T., Klebe, G., FlexS: a method for fast flexible ligand superposition. J. Med. Chem. 41 (1998), 4502–4520.
71. [71] Schneider, N., Hindle, S., Lange, G., Klein, R., Albrecht, J., Briem, H., Beyer, K., Claußen, H., Gastreich, M., Lemmen, C., Rarey, M., Substantial improvements in large-scale redocking and screening using the novel HYDE scoring function. J. Comput.-Aided Mol. Des. 26 (2012), 701–723.
72. [72] Bietz, S., Urbaczek, S., Schulz, B., Rarey, M., Protoss: a holistic approach to predict tautomers and protonation states in protein-ligand complexes. J. Cheminform, 6, 2014, 12.
73. [73] TorsionAnalyzer was developed in collaboration between F. Hoffmann-LaRoche, Switzerland, and the Center for Bioinformatics (ZBH) of the University of Hamburg: http://www.biosolveit.de/TorsionAnalyzer/.
74. [74] Schärfer, C., Schulz-Gasch, T., Ehrlich, H.C., Guba, W., Rarey, M., Stahl, M., Torsion angle preferences in drug-like chemical space: a comprehensive guide. J. Med. Chem. 56 (2013), 2016–2028.