Navigating the Chemical Space of Multitarget-Directed Ligands: From Hybrids to Fragments in Alzheimer's Disease

Molecules

Volumn 21, Issue 4, 2016, Pages

  Prati, Federica ^a,b   Cavalli, Andrea ^a,c   Bolognesi, Maria Laura ^a  

^a UNIVERSITY OF BOLOGNA   (Italy)

^b UNIVERSITY OF DUNDEE   (United Kingdom)

^c ISTITUTO ITALIANO DI TECNOLOGIA   (Italy)

Author keywords

Bace 1 inhibitors; Clioquinol; Donepezil; Galantamine; GSK 3; Inhibitors; Memantine; Multitarget drug discovery

Indexed keywords

ACETYLCHOLINESTERASE; ASPARTIC PROTEINASE; BACE1 PROTEIN, HUMAN; CHOLINESTERASE INHIBITOR; GLYCOGEN SYNTHASE KINASE 3BETA; LIGAND; N METHYL DEXTRO ASPARTIC ACID RECEPTOR; SECRETASE;

ALZHEIMER DISEASE; ANTAGONISTS AND INHIBITORS; DRUG DEVELOPMENT; DRUG EFFECTS; HUMAN; METABOLISM;

ACETYLCHOLINESTERASE; ALZHEIMER DISEASE; AMYLOID PRECURSOR PROTEIN SECRETASES; ASPARTIC ACID ENDOPEPTIDASES; CHOLINESTERASE INHIBITORS; DRUG DISCOVERY; GLYCOGEN SYNTHASE KINASE 3 BETA; HUMANS; LIGANDS; RECEPTORS, N-METHYL-D-ASPARTATE;

EID: 84968680168     PISSN: None     EISSN: 14203049     Source Type: Journal    
DOI: 10.3390/molecules21040466     Document Type: Review

References (60)

1. Csermely, P.; Agoston, V.; Pongor, S. The efficiency of multi-target drugs: The network approach might help drug design. Trends Pharmacol. Sci. 2005, 26, 178-182.
2. Hopkins, A.L. Network pharmacology: The next paradigm in drug discovery. Nat. Chem. Biol. 2008, 4, 682-690.
3. Barabasi, A.L.; Gulbahce, N.; Loscalzo, J. Network medicine: A network-based approach to human disease. Nat. Rev. Genet. 2011, 12, 56-68.
4. Zheng, H.; Fridkin, M.; Youdim, M. New approaches to treating Alzheimer's disease. Perspect. Med. Chem. 2015, 7, 1-8.
5. Prati, F.; Uliassi, E.; Bolognesi, M.L. Two diseases, one approach: Multitarget drug discovery in Alzheimer's and neglected tropical diseases. MedChemComm 2014, 5, 853-861.
6. Cavalli, A.; Bolognesi, M.L.; Minarini, A.; Rosini, M.; Tumiatti, V.; Recanatini, M.; Melchiorre, C. Multi-target-directed ligands to combat neurodegenerative diseases. J. Med. Chem. 2008, 51, 347-372.
7. Cavalli, A.; Bolognesi, M.L.; Capsoni, S.; Andrisano, V.; Bartolini, M.; Margotti, E.; Cattaneo, A.; Recanatini, M.; Melchiorre, C. A small molecule targeting the multifactorial nature of Alzheimer's disease. Angew. Chem. Int. Ed. 2007, 46, 3689-3692.
8. Bolognesi, M.L. Polypharmacology in a single drug: Multitarget drugs. Curr. Med. Chem. 2013, 20, 1639-1645.
9. Hopkins, A.L.; Mason, J.S.; Overington, J.P. Can we rationally design promiscuous drugs? Curr. Opin. Struct. Biol. 2006, 16, 127-136.
10. Morphy, R.; Rankovic, Z. Designing multiple ligands-Medicinal chemistry strategies and challenges. Curr. Pharm. Des. 2009, 15, 587-600.
11. Morphy, R.; Kay, C.; Rankovic, Z. From magic bullets to designed multiple ligands. Drug Discov. Today 2004, 9, 641-651.
12. Morphy, R.; Rankovic, Z. The physicochemical challenges of designing multiple ligands. J. Med. Chem. 2006, 49, 4961-4970.
13. Hann, M.M.; Leach, A.R.; Harper, G. Molecular complexity and its impact on the probability of finding leads for drug discovery. J. Chem. Inf. Comput. Sci. 2001, 41, 856-864.
14. Bottegoni, G.; Favia, A.D.; Recanatini, M.; Cavalli, A. The role of fragment-based and computational methods in polypharmacology. Drug Discov. Today 2012, 17, 23-34.
15. Morphy, R. The influence of target family and functional activity on the physicochemical properties of pre-clinical compounds. J. Med. Chem. 2006, 49, 2969-2978.
16. Morphy, R.; Rankovic, Z. Fragments, network biology and designing multiple ligands. Drug Discov. Today 2007, 12, 156-160.
17. Morphy, J.R.; Harris, C.J. Designing Multi-target Drugs; Royal Society of Chemistry: Cambridge, UK, 2012; Volume 21.
18. Decker, M. Recent advances in the development of hybrid molecules/designed multiple compounds with antiamnesic properties. Mini Rev. Med. Chem. 2007, 7, 221-229.
19. Viayna, E.; Sabate, R.; Munoz-Torrero, D. Dual inhibitors of beta-amyloid aggregation and acetylcholinesterase as multi-target anti-Alzheimer drug candidates. Curr. Top. Med. Chem. 2013, 13, 1820-1842.
20. Geldenhuys, W.J.; van der Schyf, C.J. Designing drugs with multi-target activity: The next step in the treatment of neurodegenerative disorders. Expert Opin. Drug Discov. 2012, 8, 115-129.
21. Leon, R.; Garcia, A.G.; Marco-Contelles, J. Recent advances in the multitarget-directed ligands approach for the treatment of Alzheimer's disease. Med. Res. Rev. 2013, 33, 139-189.
22. Agis-Torres, A.; Solhuber, M.; Fernandez, M.; Sanchez-Montero, J.M. Multi-target-directed ligands and other therapeutic strategies in the search of a real solution for Alzheimer's disease. Curr. Neuropharmacol. 2014, 12, 2-36.
23. Guzior, N.; Wieckowska, A.; Panek, D.; Malawska, B. Recent development of multifunctional agents as potential drug candidates for the treatment of Alzheimer's disease. Curr. Med. Chem. 2015, 22, 373-404.
24. Perez, D.I.; Martinez, A.; Gil, C.; Campillo, N.E. From bitopic inhibitors to multitarget drugs for the future treatment of Alzheimer's disease. Curr. Med. Chem. 2015, 22, 3789-3806.
25. Simoni, E.; Daniele, S.; Bottegoni, G.; Pizzirani, D.; Trincavelli, M.L.; Goldoni, L.; Tarozzo, G.; Reggiani, A.; Martini, C.; Piomelli, D.; et al. Combining galantamine and memantine in multitargeted, new chemical entities potentially useful in Alzheimer's disease. J. Med. Chem. 2012, 55, 9708-9721.
26. Patel, L.; Grossberg, G.T. Combination therapy for Alzheimer's disease. Drugs Aging 2011, 28, 539-546.
27. Parsons, C.G.; Danysz, W.; Dekundy, A.; Pulte, I. Memantine and cholinesterase inhibitors: Complementary mechanisms in the treatment of Alzheimer's disease. Neurotox. Res. 2013, 24, 358-369.
28. Rosini, M.; Simoni, E.; Bartolini, M.; Cavalli, A.; Ceccarini, L.; Pascu, N.; McClymont, D.W.; Tarozzi, A.; Bolognesi, M.L.; Minarini, A.; et al. Inhibition of acetylcholinesterase, beta-amyloid aggregation, and nmda receptors in Alzheimer's disease: A promising direction for the multi-target-directed ligands gold rush. J. Med. Chem. 2008, 51, 4381-4384.
29. Rook, Y.; Schmidtke, K.U.; Gaube, F.; Schepmann, D.; Wunsch, B.; Heilmann, J.; Lehmann, J.; Winckler, T. Bivalent beta-carbolines as potential multitarget anti-Alzheimer agents. J. Med. Chem. 2010, 53, 3611-3617.
30. Liu, Z.; Lv, C.; Zhao, W.; Song, Y.; Pei, D.; Xu, T. Nr2b-containing nmda receptors expression and their relationship to apoptosis in hippocampus of Alzheimer's disease-like rats. Neurochem. Res. 2012, 37, 1420-1427.
31. Mony, L.; Kew, J.N.; Gunthorpe, M.J.; Paoletti, P. Allosteric modulators of Nr2b-containing nmda receptors: Molecular mechanisms and therapeutic potential. Br. J. Pharmacol. 2009, 157, 1301-1317.
32. Chazot, P.L. The NMDA receptor Nr2b subunit: A valid therapeutic target for multiple CNS pathologies. Curr. Med. Chem. 2004, 11, 389-396.
33. Rosini, M.; Simoni, E.; Minarini, A.; Melchiorre, C. Multi-target design strategies in the context of Alzheimer's disease: Acetylcholinesterase inhibition and NMDA receptor antagonism as the driving forces. Neurochem. Res. 2014, 39, 1914-1923.
34. Lopes, J.P.; Tarozzo, G.; Reggiani, A.; Piomelli, D.; Cavalli, A. Galantamine potentiates the neuroprotective effect of memantine against NMDA-induced excitotoxicity. Brain Behav. 2013, 3, 67-74.
35. Takada-Takatori, Y.; Kume, T.; Sugimoto, M.; Katsuki, H.; Sugimoto, H.; Akaike, A. Acetylcholinesterase inhibitors used in treatment of Alzheimer's disease prevent glutamate neurotoxicity via nicotinic acetylcholine receptors and phosphatidylinositol 3-kinase cascade. Neuropharmacology 2006, 51, 474-486.
36. Prati, F.; Bergamini, C.; Fato, R.; Soukup, O.; Korabecny, J.; Andrisano, V.; Bartolini, M.; Bolognesi, M.L. Novel 8-hydroxyquinoline derivatives as multitarget compounds for the treatment of Alzheimer's disease. ChemMedChem 2016.
37. Lovell, M.A.; Robertson, J.D.; Teesdale, W.J.; Campbell, J.L.; Markesbery, W.R. Copper, iron and zinc in Alzheimer's disease senile plaques. J. Neurol. Sci. 1998, 158, 47-52.
38. Suh, S.W.; Jensen, K.B.; Jensen, M.S.; Silva, D.S.; Kesslak, P.J.; Danscher, G.; Frederickson, C.J. Histochemically-reactive zinc in amyloid plaques, angiopathy, and degenerating neurons of Alzheimer's diseased brains. Brain Res. 2000, 852, 274-278.
39. Curtain, C.C.; Ali, F.; Volitakis, I.; Cherny, R.A.; Norton, R.S.; Beyreuther, K.; Barrow, C.J.; Masters, C.L.; Bush, A.I.; Barnham, K.J. Alzheimer's disease amyloid-beta binds copper and zinc to generate an allosterically ordered membrane-penetrating structure containing superoxide dismutase-like subunits. J. Biol. Chem. 2001, 276, 20466-20473.
40. Smith, D.G.; Cappai, R.; Barnham, K.J. The redox chemistry of the Alzheimer's disease amyloid beta peptide. Biochim. Biophys. Acta 2007, 1768, 1976-1990.
41. Lim, K.H.; Kim, Y.K.; Chang, Y.T. Investigations of the molecular mechanism of metal-induced abeta (1-40) amyloidogenesis. Biochemistry 2007, 46, 13523-13532.
42. Cuajungco, M.P.; Goldstein, L.E.; Nunomura, A.; Smith, M.A.; Lim, J.T.; Atwood, C.S.; Huang, X.; Farrag, Y.W.; Perry, G.; Bush, A.I. Evidence that the beta-amyloid plaques of Alzheimer's disease represent the redox-silencing and entombment of abeta by zinc. J. Biol. Chem. 2000, 275, 19439-19442.
43. Adlard, P.A.; Cherny, R.A.; Finkelstein, D.I.; Gautier, E.; Robb, E.; Cortes, M.; Volitakis, I.; Liu, X.; Smith, J.P.; Perez, K.; et al. Rapid restoration of cognition in Alzheimer's transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial abeta. Neuron 2008, 59, 43-55.
44. Cherny, R.A.; Atwood, C.S.; Xilinas, M.E.; Gray, D.N.; Jones, W.D.; McLean, C.A.; Barnham, K.J.; Volitakis, I.; Fraser, F.W.; Kim, Y.; et al. Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice. Neuron 2001, 30, 665-676.
45. Kaur, D.; Yantiri, F.; Rajagopalan, S.; Kumar, J.; Mo, J.Q.; Boonplueang, R.; Viswanath, V.; Jacobs, R.; Yang, L.; Beal, M.F.; et al. Genetic or pharmacological iron chelation prevents mptp-induced neurotoxicity in vivo: A novel therapy for Parkinson's disease. Neuron 2003, 37, 899-909.
46. Nguyen, T.; Hamby, A.; Massa, S.M. Clioquinol down-regulates mutant huntingtin expression in vitro and mitigates pathology in a Huntington's disease mouse model. Proc. Natl. Acad. Sci. USA 2005, 102, 11840-11845.
47. Zatta, P.; Drago, D.; Bolognin, S.; Sensi, S.L. Alzheimer's disease, metal ions and metal homeostatic therapy. Trends Pharmacol. Sci. 2009, 30, 346-355.
48. Prachayasittikul, V.; Prachayasittikul, S.; Ruchirawat, S. 8-hydroxyquinolines: A review of their metal chelating properties and medicinal applications. Drug Des. Devel. Ther. 2013, 7, 1157-1178.
49. Fernandez-Bachiller, M.I.; Perez, C.; Gonzalez-Munoz, G.C.; Conde, S.; Lopez, M.G.; Villarroya, M.; Garcia, A.G.; Rodriguez-Franco, M.I. Novel tacrine-8-hydroxyquinoline hybrids as multifunctional agents for the treatment of Alzheimer's disease, with neuroprotective, cholinergic, antioxidant, and copper-complexing properties. J. Med. Chem. 2010, 53, 4927-4937.
50. Zheng, H.; Fridkin, M.; Youdim, M. From single target to multitarget/network therapeutics in Alzheimer's therapy. Pharmaceuticals 2014, 7, 113-135.
51. Prati, F.; de Simone, A.; Bisignano, P.; Armirotti, A.; Summa, M.; Pizzirani, D.; Scarpelli, R.; Perez, D.I.; Andrisano, V.; Perez-Castillo, A.; et al. Multitarget drug discovery for Alzheimer's disease: Triazinones as bace-1 and gsk-3beta inhibitors. Angew. Chem. Int. Ed. 2015, 54, 1578-1582.
52. 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, 4156-4180.
53. Ghosh, A.K.; Osswald, H.L. Bace1 (beta-secretase) inhibitors for the treatment of Alzheimer's disease. Chem. Soc. Rev. 2014, 43, 6765-6813.
54. Kramer, T.; Schmidt, B.; Lo Monte, F. Small-molecule inhibitors of gsk-3: Structural insights and their application to Alzheimer's disease models. Int. J. Alzheimers Dis. 2012, 2012, 381029.
55. Pena-Altamira, E.; Prati, F.; Massenzio, F.; Virgili, M.; Contestabile, A.; Bolognesi, M.L.; Monti, B. Changing paradigm to target microglia in neurodegenerative diseases: From anti-inflammatory strategy to active immunomodulation. Expert Opin. Ther. Targets 2016, 20, 627-640.
56. Prati, F.; de Simone, A.; Armirotti, A.; Summa, M.; Pizzirani, D.; Scarpelli, R.; Bertozzi, S.M.; Perez, D.I.; Andrisano, V.; Perez-Castillo, A.; et al. 3,4-Dihydro-1,3,5-triazin-2(1h)-ones as the first dual bace-1/gsk-3beta fragment hits against Alzheimer's disease. ACS Chem. Neurosci. 2015, 6, 1665-1682.
57. Banik, A.; Brown, R.E.; Bamburg, J.; Lahiri, D.K.; Khurana, D.; Friedland, R.P.; Chen, W.; Ding, Y.; Mudher, A.; Padjen, A.L.; et al. Translation of pre-clinical studies into successful clinical trials for Alzheimer's disease: What are the roadblocks and how can they be overcome? J. Alzheimers Dis. 2015, 47, 815-843.
58. Herrup, K. The case for rejecting the amyloid cascade hypothesis. Nat. Neurosci. 2015, 18, 794-799.
59. Tang, S.; Xie, M.; Cao, N.; Ding, S. Patient-specific induced pluripotent stem cells for disease modeling and phenotypic drug discovery. J. Med. Chem. 2016, 59, 2-15.
60. Cummings, J.L.; Morstorf, T.; Zhong, K. Alzheimer's disease drug-development pipeline: Few candidates, frequent failures. Alzheimers Res. Ther. 2014, 6, 37.