The multifactorial nature of major neurodegenerative diseases and the current failures of the different drugs in clinical trials represent the logical foundation for a multi-target drug discovery approach to combat these devastating diseases [1]. As additional positive points, the simplification of the therapeutic regimen and a lower risk of polypharmacy in geriatric population further strengthen its validity in comparison with drug combinations [2]. However, at this moment the afore-mentioned advantages can be outweighed by the difficulties still experienced by medicinal chemists in the discovery and development of novel multi-target drugs (MTDs). In fact, albeit methods such as fragment-based and computational drug discovery are showing promising potential in accelerating the process, the hit identification and optimization stages of MTDs still poses more challenges than those of single-target drugs. Besides these methods, the ligand-based approach is still the method of choice, especially in the academia. In most cases, two starting structures and/or their pharmacophoric elements are combined to incorporate both activities in a new single chemical entity. Alternatively, a single fragment able to recognize even with modest affinity more than one target (dubbed by us “universal template”) can serve as core scaffold to be decorated with appendages to generate higher affinity compounds [3]. Herein, we discuss several examples of both types of compounds, taken from our own research devoted to the rational discovery of MTDs against Alzheimer’s and prion diseases. [1] 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, 347-72. [2] Bolognesi, M. L.; Matera, R.; Minarini, A.; Rosini, M.; Melchiorre, C. Alzheimer's disease: new approaches to drug discovery. Curr Opin Chem Biol, 2009, 13, 303-8. [3] Discovery of Multi-Target Agents for Neurological Diseases via Ligand Design. Bolognesi, M.L., Melchiorre, C., Van der Schyf, C.J., and Youdim, M.B.H. in: RSC Drug Discovery Series No. 21, Designing Multi-Target Drugs. Edited by: J. Richard Morphy and C. John Harris, 2012, Royal Society of Chemistry, United Kingdom, pp. 290-315
Discovery of multi-target probes for neurodegenerative diseases via ligand design
BOLOGNESI, MARIA LAURA
2012
Abstract
The multifactorial nature of major neurodegenerative diseases and the current failures of the different drugs in clinical trials represent the logical foundation for a multi-target drug discovery approach to combat these devastating diseases [1]. As additional positive points, the simplification of the therapeutic regimen and a lower risk of polypharmacy in geriatric population further strengthen its validity in comparison with drug combinations [2]. However, at this moment the afore-mentioned advantages can be outweighed by the difficulties still experienced by medicinal chemists in the discovery and development of novel multi-target drugs (MTDs). In fact, albeit methods such as fragment-based and computational drug discovery are showing promising potential in accelerating the process, the hit identification and optimization stages of MTDs still poses more challenges than those of single-target drugs. Besides these methods, the ligand-based approach is still the method of choice, especially in the academia. In most cases, two starting structures and/or their pharmacophoric elements are combined to incorporate both activities in a new single chemical entity. Alternatively, a single fragment able to recognize even with modest affinity more than one target (dubbed by us “universal template”) can serve as core scaffold to be decorated with appendages to generate higher affinity compounds [3]. Herein, we discuss several examples of both types of compounds, taken from our own research devoted to the rational discovery of MTDs against Alzheimer’s and prion diseases. [1] 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, 347-72. [2] Bolognesi, M. L.; Matera, R.; Minarini, A.; Rosini, M.; Melchiorre, C. Alzheimer's disease: new approaches to drug discovery. Curr Opin Chem Biol, 2009, 13, 303-8. [3] Discovery of Multi-Target Agents for Neurological Diseases via Ligand Design. Bolognesi, M.L., Melchiorre, C., Van der Schyf, C.J., and Youdim, M.B.H. in: RSC Drug Discovery Series No. 21, Designing Multi-Target Drugs. Edited by: J. Richard Morphy and C. John Harris, 2012, Royal Society of Chemistry, United Kingdom, pp. 290-315I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
