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Alzheimer’s Disease, the “One-Molecule, One-Target” Paradigm, and the Multitarget Directed Ligand Approach María Jesús Oset-Gasque†,‡ and José Marco-Contelles*,§ †
Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Plaza Ramón y Cajal s/n, Ciudad Universitaria, 28040 Madrid, Spain ‡ Instituto de Investigación en Neuroquı ́mica, Universidad Complutense de Madrid, Ciudad Universitaria, 28040 Madrid, Spain § Laboratory of Medicinal Chemistry (IQOG, CSIC), 3, Juan de la Cierva, 28006-Madrid, Spain ABSTRACT: No selective drugs exist, and we have been designing, synthesizing, and evaluating multitarget-directed ligands since the beginning of modern medicinal chemistry, without knowing it, most possibly. The challenge to discover the efficient Multi-Target Small Molecules (MTSMs) for Alzheimer’s disease (AD) therapy implies to identify the key combination of biological targets to modulate them, thus including in the design the corresponding pharmacophoric groups able to do it. Universal and polyvalent pharmacophoric groups, able to modulate diverse receptors or enzymatic systems, would simplify the drug discovery process leading to new and more efficient MTSMs for AD. KEYWORDS: Alzheimer’s disease, multitarget-small molecules, selective drugs ”Les Femmes Savantes” a play by Molière, when the realized they were talking currently in prose..., without knowing it. Nevertheless, the concept of MTDLs has been assumed at least in academic scenarios, and produced an increasing number of new promising molecules for the treatment of AD. But then, what is new? The question is pertinent, and the answer simple: now, the medicinal chemist decides a priori which and how many pharmacophoric groups have to be assembled and inserted in the new family of molecules, based on the type and number of biological targets, implemented in the progress and development of the pathology, to modulate them. And this is the key point: which and how many biological targets? Until now, all the efforts in this area have met with failure, confirming the challenge we are facing. We see the pharmacological properties of a given molecule as a book already written and edited, whose pages are only open and accessible to the scientific community when one scientist discovers and reports its qualitative and quantitative data. In our recent preliminary communication on the topic, we could consequently suggest that contilisant, at least, is a tripotent agent for AD, able to inhibit the ChEs/MAOs enzymes and modulate the H3R selectively,4 whose total pharmacological properties, either positive or negative for AD therapy, are still waiting to be evaluated and discovered. The success of a small molecule for AD therapy will depend on this selection and choice. In this context, another frustating lieu commun, continuously heard and written, points out that as we do not yet know the etiology of AD, it will be impractical to find the correct therapy. New hypotheses have been incorporated to the classical cholinergic, β-amyloid, tau, oxidative stress, biometal chelating agents. Thus, the challenge among molecular biologists is to find the real answer to this problem (Figure 1). However, for
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n February 14, 2018, 10 years will have elapsed since Melchiorre and colleagues published the famous review article in the Journal of Medicinal Chemistry,1 where they advanced and defined the term multitarget-directed ligands (MTDLs) in order to describe “...those compounds that are effective in treating complex diseases because of their ability to interact with the multiple targets thought to be responsible for the disease pathogenesis...”,2 in clear contrast and opposition to drugs developed under the “one-molecule, one-target” paradigm,3 whose presumed selectivity should be a drawback from the therapeutic point of view comparing to MTDLs, for the potential treatment of complex, multifactorial diseases, such as cancer or Alzheimer’s disease (AD). Not surprisingly, the MTDL strategy has now been incorporated in routine therapeutic drug design, and a considerable number of compounds have been described in the last 10 years, based on this therapeutic approach. In the case of AD, it has been stated that the very limited success of acetylcholinesterase inhibitors (AChEIs), such as donepezil, rivastigmine, or galantamine, the only currently administered drugs for AD therapy, is due to the fact that “...by improving cognitive, behavioral, and functional impairments, they seem unable to address the molecular mechanisms that underlie the pathogenic processes...”1 However, a new perspective is possible. For us, it is clear donepezil, for instance, is not the best drug for AD, not precisely for its selective AChE inhibition profile, but for the fact that its whole reported pharmacological profile, or still to be discovered, along with its physicochemical properties, are not sufficient to cure AD patients. Consequently, there are no selective molecules, or “magic bullets”,3 and all the described small molecules, or yet to come, to treat complex, multifactorial diseases, are MTDLs per se. Consequently, we have been designing, synthesizing, and evaluating MTDLs since ever, most possibly, without knowing it. The real expectations raised by Melchiorre and colleagues in 2008,1 remind us the happiness of © XXXX American Chemical Society
Received: February 13, 2018 Accepted: February 14, 2018
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DOI: 10.1021/acschemneuro.8b00069 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
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ACS Chemical Neuroscience
Figure 1. Some of the biological targets involved in AD pathology.
Figure 2. Ideal and efficient MTSM for AD therapy, showing their corresponding pharmacophoric groups (PG).
the range of the ADMET limits, showing antioxidant, neuroprotective, brain permeable properties and test them in suitable in vivo models. The good news is that we know that simple and unique pharmacophoric groups can provide effective pharmacological responses for diverse receptors or enzymatic systems, therefore enormously simplifying the design (Figure 2). Complex, indeed, but not impossible: inspiration and hard work, based on brilliant ideas put in practice by simple, short, and efficient synthetic schemes, and committed and cooperative work among medicinal chemists, pharmacologists, and biochemists should possibly lead to new and more efficient MTSMs for AD therapy.
us, it is certainly clear we do not know when and why AD shows up, but the origin of AD is simple, and resumed in one word: age. AD is a disease of aging. Consequently, the observed AD manifestations result from the degeneration and failure of all the biological events taking place in the CNS connected with the cognitive functions, memory, and so forth. The extent determines whether one has just forgotten something, or suffers from dementia, or is an AD patient. These symbolize diverse and gradual perspectives of the same picture. No single hypothesis would be able to provide the key for the AD origin. The search for the AD Holy Grail would fail, as it does not exist. It is the combined and simultaneous failure of a number of biological events that cause on what we know as AD. As a result, the solution is simple, but impossible: the efficient small molecule for AD should modulate all the receptors or enzymatic systems, as well as the oxidative stress, inflammation, Ca dyshomeostasis, and so forth involved in the pathology (Figure 2). Perhaps some sophisticated computer program could give an answer. Who knows? Presently, for the moment, for medicinal chemists in the academia, the only choice is to build new multitarget small molecules (MTSMs) in
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AUTHOR INFORMATION
Corresponding Author
*Tel: 34 91 5622900. Ext: 371. Fax: 34 91 564 48 53. E-mail:
[email protected]. ORCID
José Marco-Contelles: 0000-0003-0690-0328 B
DOI: 10.1021/acschemneuro.8b00069 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
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The authors declare no competing financial interest.
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REFERENCES
(1) Cavalli, A., Bolognesi, M. L., Minarini, A., Rosini, M., Tumiatti, V., Recanatini, M., and Melchiorre, C. (2008) Multi-target-directed ligands to combat neurodegenerative diseases. J. Med. Chem. 51, 347− 372 This article has 485 citations based on SciFinder (03/01/2018).. (2) For a pionner, similar concept to MTDL, see: Morphy, R., and Rankovic, Z. (2005) Designed multiple ligands. An emerging drug discovery paradigm. J. Med. Chem. 48, 6523−6543. (3) Morphy, R., Kay, C., and Rankovic, Z. (2004) From magic bullets to designed multiple ligands. Drug Discovery Today 9, 641−651. (4) Bautista-Aguilera, O., Hagenow, S., Palomino-Antolín, A., FarréAlins, V., Ismaili, L., Joffrin, P.-L., Jimeno, M. L., Soukup, O., Janockova, J., Kalinowsky, L., Proschak, E., Iriepa, I., Moraleda, I., Schwed, J. S., Romero Martínez, A., López-Muñoz, F., Chioua, M., Egea, J., Ramsay, R. R., Marco-Contelles, J., and Stark, H. (2017) Multitarget-directed ligands combining cholinesterase and monoamine oxidase inhibition with histamine H3R antagonism for neurodegenerative diseases. Angew. Chem., Int. Ed. 56, 12765−12769.
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DOI: 10.1021/acschemneuro.8b00069 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
