Viewpoint Cite This: ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
pubs.acs.org/chemneuro
Facts, Results, and Perspectives of the Current Alzheimer’s Disease Research Jose ́ Marco-Contelles*
ACS Chem. Neurosci. Downloaded from pubs.acs.org by 5.62.155.195 on 02/04/19. For personal use only.
Laboratory of Medicinal Chemistry, Institute of General Organic Chemistry, Spanish National Research Council, Juan de la Cierva, 3, 28006-Madrid, Spain ABSTRACT: Credit should be granted to medicinal chemists with a solid background in organic chemistry and computational chemistry, able to read, understand, and discuss the biological data, in order to design new and more efficient therapeutic approaches for Alzheimer’s disease KEYWORDS: Aβ hypothesis, Alzheimer’s disease, disease-modifying therapy approach, multitarget small molecules, symptomatic-disease approach, tau hypothesis ast year, in my first Viewpoint contribution,1 we focused on the concept of multitarget directed ligands (MTDLs), the current efforts to find the origin of Alzheimer’s disese (AD), and suggested to forget the erroneous “one-target-onemolecule” concept, as all molecules are per se MTDLs. We then proposed to use the alternative multitarget small molecules (MTSMs) concept to clearly define what the medicinal chemists hope and expect: small molecules designed under Lipinski’s umbrella, and its new refinements.1 We also reasoned the pointless efforts to find the Holy Grail of the AD origin as the first step to find the correct therapy for AD, a task that has concentrated and still concentrates efforts and huge amounts of public resources, from thousands of molecular biologists and biochemists around the world.1 Hopefully, mankind has survived all the pests, plagues, and diseases without knowing the biological origin of the corresponding pathologies. Basically, for the very simple fact that, by chance or serendipity, but surely always after hard work, in the last two centuries, organic-medicinal chemists have prepared (or isolated from natural sources) molecules to cure people, without knowing the origin, mechanisms, and signaling events of the biological targets involved. And the same will certainly happen for AD, although in this case the very complex nature of the disease has prevented it until now. The fact is that, for AD, the gold-standard-beta-amyloid gospel has been a total failure. But they are chameleons, and while half of priests are now looking for new biomarkers to discover when the disease starts (it remains to find out what they are going to do later, once detected...), the other half has moved to and are preaching the second new gospel of the tauopathies. Excellent and good luck, but it would be now be opportune to remember that early attempts based on Tideglusib, a GSK-3β inhibitor, failed in the very early clinical studies. The fact is that we do not know the origin of the disease, and consequently, the presumably more scientifically sound “disease-modif ying therapies”, by opposition to the rude “symptomatic-disease approaches”, does not justify any conceptual supremacy, and does not resist any more a critical analysis, much more when the only drugs in the clinic are endowed with ChE inhibition activity. So, the point would be not the color of the cats, but whether they can hunt the mice of
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© XXXX American Chemical Society
AD. I would propose not to use nevermore these diverse, misleading type of conceptual therapeutic approaches.2 I confess that, after more than 20 years in the field, I have never designed a MTSM for AD therapy, targeted to modulate Aβ. I do not care. On the contrary, I have on purpose designed them to rescue and recover the level of neurotransmitters involved in the cognitive processes by inhibition of, at least, cholinesterases and monoamine oxidases, or by modulating histamine 3 and sigma 1 receptors, but have observed that Contilisant (Figure 1), our most advanced lead-compound on
Figure 1. Structure and pharmacological properties of MTSM Contilisant.
this venture, efficiently promotes in vivo the procognitive effects impaired by the effect of Aβ, overcoming Donepezil.3 As highlighted in red, in Figure 1, the same “piperidinepropyloxy” pharmacophore motif would be responsible for binding the S1R, H3R and inhibiting the ChEs, simplifying the structure of the MTSM, doing more with less. Thus, would not the formation and aggregation of Aβ be a consequence of the low neurotransmitters level in the brain of aging people, and not the origin of AD? Not surprisingly, as the reader can guess, I never could attract the interest of any pharmaceutical company for my MTSMs, obsessed as they are by the sound-unsuccessful-gold-Aβ-hypothesis, and I have felt the Received: January 15, 2019 Accepted: January 18, 2019
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DOI: 10.1021/acschemneuro.9b00034 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
Viewpoint
ACS Chemical Neuroscience misunderstanding, if not the scorn, of my molecular biologist colleagues. However, there is always a place for hope. The fact that Lundbeck A/S is seriously betting for 5-HT6 antagonists in combination with Donepezil for the symptomatic treatment of AD suggests that a different, and most possibly successful therapeutic strategy is possible,4 with the only question being why a combination of drugs instead of the single multitarget formulation.1 In other words, why do pharmaceutical companies not invest in MTSMs for complex diseases, while in academia this is a very long-accepted transition? I’m afraid that the impressive number of patent-protected advanced studies coming from the academia, describing very interesting hit-derivatives for AD, will rest in peace in the cemeteries of the most prestigious journals. I humbly suggest that the pharmaceuticals, or public research institutions, check and read carefully what is being published, where they can find real treasures of possible new lead drugs. In summary, I conclude from all these facts and results that when the strategic therapeutic decisions for AD therapy, in the pharmaceutical companies or biotechs, have been decided and managed by molecular biologists, the failure has been a guaranteed fact. I prompt them to face self-criticism for their responsibility in this regard. Conversely, I strongly believe in the power of traditional, old-fashioned passion for the synthesis of new targeted molecules (I’m sorry!), and in medicinal chemists, in close collaboration with biologists, in order to find new and more efficient therapeutic approaches for AD.5
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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 Funding
J.M.-C. thanks MINECO (Government of Spain) (SAF201565586-R) and Universidad Camilo José Cela (NitroStroke project, 2015-12) for support. Notes
Views expressed in this viewpoint are those of the author and not necessarily the views of the ACS. The author declares no competing financial interest.
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REFERENCES
(1) Oset-Gasque, M. J., and Marco-Contelles, J. (2018) Alzheimer’s disease, the “One-Molecule, one-Target” Paradigm, and the multitarget directed ligand approach. ACS Chem. Neurosci. 9, 401−403. (2) Wicke, K., Bespalov, A., and Haupt, A. (2015) Investigational drugs targeting 5- HT6 receptors for the treatment of Alzheimer’s disease. Expert Opin. Invest. Drugs 24, 1515−28. (3) Bautista-Aguilera, O. M., Budni, J., Mina, F., Behenck Medeiros, E., Deuther-Conrad, W., Entrena, J. M., Moraleda, I., Iriepa, I., LópezMuñoz, F., and Marco-Contelles, J. (2018) Contilisant a tetratarget small molecule for Alzheimer’s disease therapy combining cholinesterase, monoamine oxidase inhibition and H3R antagonism with sigma 1R agonism profile. J. Med. Chem. 61, 6937−6943. (4) de Jong, I. E. M., and Moerk, A. (2017) Antagonism of the 5HT6 receptor - Preclinical rationale for the treatment of Alzheimer’s disease. Neuropharmacology 125, 50−63. (5) Webb, T. R. (2018) Improving the efficiency of the drug development by expanding the scope of the role of medicinal chemists in drug discovery. ACS Med. Chem. Lett. 9, 1153−1155. B
DOI: 10.1021/acschemneuro.9b00034 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
