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Facing Novel Challenges in Drug Discovery

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 January 2020) | Viewed by 54068

Special Issue Editors


E-Mail Website1 Website2
Guest Editor
Laboratory of Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Biomedicine (IBUB), University of Barcelona, Avenue Joan XXIII, 27-31, E-08028 Barcelona, Spain
Interests: multitarget anti-Alzheimer agents; hybrid compounds; cholinesterase inhibitors; amyloid anti-aggregating compounds; BACE-1 inhibitors; antiprotozoan compounds
Special Issues, Collections and Topics in MDPI journals

E-Mail Website
Guest Editor
Department of Nutrition, Food Sciences and Gastronomy, Faculty of Pharmacy and Food Sciences, Institute of Biomedicine (IBUB) and Institute of Theoretical and Computational Chemistry (IQTC), University of Barcelona, Av. Prat de la Riba 171, E-08921 Santa Coloma de Gramenet, Spain
Interests: computational biology; molecular modeling; molecular simulations; drug design; multitarget compounds; neurodegeneration; antiviral compounds
Special Issues, Collections and Topics in MDPI journals

E-Mail Website
Guest Editor
1. Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine (IBUB), University of Barcelona, Barcelona, Spain
2. Pediatric Oncology Program, Institut de Recerca Sant Joan de Déu (IR SJD), Esplugues de Llobregat, Barcelona, Spain
3. Oncology Program, National Biomedical Research Institute of Liver and Gastrointestinal Diseases (CIBER EHD), Instituto de Salud Carlos III, Madrid, Spain
Interests: drug transporters; nucleoside analogs; anticancer therapy; antiviral therapy; mechanisms of drug action; nucleotide metabolism; oncogenesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Medicinal chemistry must continuously evolve to face the novel challenges that arise from the steady trickle of scientific breakthroughs. These advances have a profound impact on any phase of the drug discovery process, from the identification of novel biological targets or the molecular bases of drug action to the development of innovative technologies and disruptive approaches with the potential to speed up and reduce the costs associated with the development of new drugs.

This Special Issue is related to the “2nd Molecules Medicinal Chemistry Symposium (MMCS2019)”, which will be held 15–17 May, 2019, at the AXA Auditorium in Barcelona, Spain. The symposium will discuss current challenges in the drug discovery field, while reporting novel and revisited drug discovery approaches for particularly challenging diseases (cancer in this edition) and medicinal chemistry stories about recently implemented projects in target and hit identification, hit-to-lead optimization, tuning of physicochemical and pharmacokinetic properties, preclinical and clinical development, etc.

The symposium participants, as well as all researchers working in the field, are cordially invited to contribute original research papers, short communications, or reviews to this Special Issue of Molecules, reporting on recent innovative medicinal chemistry projects, particularly (but not only) on the design and development of novel anticancer drugs, protein degradation inducers, target-guided synthesis of bioactive compounds, and new targets and drug candidates. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on the journal website.

Prof. Dr. Diego Muñoz-Torrero
Prof. Dr. F. Javier Luque
Prof. Dr. Marçal Pastor-Anglada
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • drug discovery
  • drug design
  • drug synthesis
  • cancer drug discovery
  • protein degradation inducers
  • target-guided synthesis
  • novel biological targets
  • novel drugs

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Published Papers (11 papers)

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Research

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15 pages, 2721 KiB  
Article
Investigation of Anti-Inflammatory Potential of N-Arylcinnamamide Derivatives
by Jan Hošek, Jiří Kos, Tomáš Strhársky, Lucie Černá, Pavel Štarha, Ján Vančo, Zdeněk Trávníček, Ferdinand Devínsky and Josef Jampílek
Molecules 2019, 24(24), 4531; https://doi.org/10.3390/molecules24244531 - 11 Dec 2019
Cited by 13 | Viewed by 3389
Abstract
A series of sixteen ring-substituted N-arylcinnamanilides, previously described as highly antimicrobially effective against a wide spectrum of bacteria and fungi, together with two new derivatives from this group were prepared and characterized. Moreover, the molecular structure of (2E)-N-(2-bromo-5-fluorophenyl)-3-phenylprop-2-enamide [...] Read more.
A series of sixteen ring-substituted N-arylcinnamanilides, previously described as highly antimicrobially effective against a wide spectrum of bacteria and fungi, together with two new derivatives from this group were prepared and characterized. Moreover, the molecular structure of (2E)-N-(2-bromo-5-fluorophenyl)-3-phenylprop-2-enamide as a model compound was determined using single-crystal X-ray analysis. All the compounds were tested for their anti-inflammatory potential, and most tested compounds significantly attenuated the lipopolysaccharide-induced NF-κB activation and were more potent than the parental cinnamic acid. (2E)-N-[2-Chloro-5-(trifluoromethyl)phenyl]-3-phenylprop-2-enamide, (2E)-N-(2,6-dibromophenyl)- 3-phenylprop-2-enamide, and (2E)-N-(2,5-dichlorophenyl)-3-phenylprop-2-enamide demonstrated the highest inhibition effect on transcription factor NF-κB at the concentration of 2 µM and showed a similar effectiveness as the reference drug prednisone. Several compounds also decreased the level of TNF-α. Nevertheless, subsequent tests showed that the investigated compounds affect neither IκBα level nor MAPKs activity, which suggests that the N-arylcinnamanilides may have a different mode of action to prednisone. The modification of the C(2,5)ʹ or C(2,6)ʹ positions of the anilide core by rather lipophilic and bulky moieties seems to be preferable for the anti-inflammatory potential of these compounds. Full article
(This article belongs to the Special Issue Facing Novel Challenges in Drug Discovery)
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12 pages, 676 KiB  
Article
Design, Synthesis, and Structural Characterization of Novel Diazaphenothiazines with 1,2,3-Triazole Substituents as Promising Antiproliferative Agents
by Beata Morak-Młodawska, Krystian Pluta, Małgorzata Latocha, Małgorzata Jeleń and Dariusz Kuśmierz
Molecules 2019, 24(23), 4388; https://doi.org/10.3390/molecules24234388 - 30 Nov 2019
Cited by 13 | Viewed by 2998
Abstract
A series of novel 1,2,3-triazole-diazphenothiazine hybrids was designed, synthesized, and evaluated for anticancer activity against four selected human tumor cell lines (SNB-19, Caco-2, A549, and MDA-MB231). The majority of the synthesized compounds exhibited significant potent activity against the investigated cell lines. Among them, [...] Read more.
A series of novel 1,2,3-triazole-diazphenothiazine hybrids was designed, synthesized, and evaluated for anticancer activity against four selected human tumor cell lines (SNB-19, Caco-2, A549, and MDA-MB231). The majority of the synthesized compounds exhibited significant potent activity against the investigated cell lines. Among them, compounds 1d and 4c showed excellent broad spectrum anticancer activity, with IC50 values ranging from 0.25 to 4.66 μM and 0.25 to 6.25 μM, respectively. The most promising compound 1d, possessing low cytotoxicity against normal human fibroblasts NHFF, was used for gene expression analysis using reverse transcription–quantitative real-time PCR (RT–qPCR). The expression of H3, TP53, CDKN1A, BCL-2, and BAX genes revealed that these compounds inhibited the proliferation in all cells (H3) and activated mitochondrial events of apoptosis (BAX/BCL-2). Full article
(This article belongs to the Special Issue Facing Novel Challenges in Drug Discovery)
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16 pages, 2576 KiB  
Article
A Prospective Repurposing of Dantrolene as a Multitarget Agent for Alzheimer’s Disease
by Isabella Bolognino, Nicola Giangregorio, Leonardo Pisani, Modesto de Candia, Rosa Purgatorio, Annamaria Tonazzi, Cosimo Damiano Altomare, Saverio Cellamare and Marco Catto
Molecules 2019, 24(23), 4298; https://doi.org/10.3390/molecules24234298 - 25 Nov 2019
Cited by 21 | Viewed by 5897
Abstract
The orphan drug dantrolene (DAN) is the only therapeutic treatment for malignant hyperthermia (MH), a pharmacogenetic pathology affecting 0.2 over 10,000 people in the EU. It acts by inhibiting ryanodine receptors, which are responsible for calcium recruitment in striatal muscles and brain. Because [...] Read more.
The orphan drug dantrolene (DAN) is the only therapeutic treatment for malignant hyperthermia (MH), a pharmacogenetic pathology affecting 0.2 over 10,000 people in the EU. It acts by inhibiting ryanodine receptors, which are responsible for calcium recruitment in striatal muscles and brain. Because of its involvement in calcium homeostasis, DAN has been successfully investigated for its potential as neuroprotecting small molecule in several animal models of Alzheimer’s disease (AD). Nevertheless, its effects at a molecular level, namely on putative targets involved in neurodegeneration, are still scarcely known. Herein, we present a prospective study on repurposing of DAN involving, besides the well-known calcium antagonism, inhibition of monoamine oxidase B and acetylcholinesterase, cytoprotection from oxidative insult, and activation of carnitine/acylcarnitine carrier, as concurring biological activities responsible for neuroprotection. Full article
(This article belongs to the Special Issue Facing Novel Challenges in Drug Discovery)
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22 pages, 10011 KiB  
Article
Towards the Development of an In vivo Chemical Probe for Cyclin G Associated Kinase (GAK)
by Christopher R. M. Asquith, James M. Bennett, Lianyong Su, Tuomo Laitinen, Jonathan M. Elkins, Julie E. Pickett, Carrow I. Wells, Zengbiao Li, Timothy M. Willson and William J. Zuercher
Molecules 2019, 24(22), 4016; https://doi.org/10.3390/molecules24224016 - 6 Nov 2019
Cited by 13 | Viewed by 3882
Abstract
SGC-GAK-1 (1) is a potent, selective, cell-active chemical probe for cyclin G-associated kinase (GAK). However, 1 was rapidly metabolized in mouse liver microsomes by cytochrome P450-mediated oxidation, displaying rapid clearance in liver microsomes and in mice, which limited its utility in [...] Read more.
SGC-GAK-1 (1) is a potent, selective, cell-active chemical probe for cyclin G-associated kinase (GAK). However, 1 was rapidly metabolized in mouse liver microsomes by cytochrome P450-mediated oxidation, displaying rapid clearance in liver microsomes and in mice, which limited its utility in in vivo studies. Chemical modifications of 1 that improved metabolic stability, generally resulted in decreased GAK potency. The best analog in terms of GAK activity in cells was 6-bromo-N-(1H-indazol-6-yl)quinolin-4-amine (35) (IC50 = 1.4 μM), showing improved stability in liver microsomes while still maintaining a narrow spectrum activity across the kinome. As an alternative to scaffold modifications we also explored the use of the broad-spectrum cytochrome P450 inhibitor 1-aminobenzotriazole (ABT) to decrease intrinsic clearance of aminoquinoline GAK inhibitors. Taken together, these approaches point towards the development of an in vivo chemical probe for the dark kinase GAK. Full article
(This article belongs to the Special Issue Facing Novel Challenges in Drug Discovery)
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34 pages, 32356 KiB  
Article
New Hydrazinothiazole Derivatives of Usnic Acid as Potent Tdp1 Inhibitors
by Aleksander S. Filimonov, Arina A. Chepanova, Olga A. Luzina, Alexandra L. Zakharenko, Olga D. Zakharova, Ekaterina S. Ilina, Nadezhda S. Dyrkheeva, Maxim S. Kuprushkin, Anton V. Kolotaev, Derenik S. Khachatryan, Jinal Patel, Ivanhoe K.H. Leung, Raina Chand, Daniel M. Ayine-Tora, Johannes Reynisson, Konstantin P. Volcho, Nariman F. Salakhutdinov and Olga I. Lavrik
Molecules 2019, 24(20), 3711; https://doi.org/10.3390/molecules24203711 - 15 Oct 2019
Cited by 37 | Viewed by 4341
Abstract
Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a promising therapeutic target in cancer therapy. Combination chemotherapy using Tdp1 inhibitors as a component can potentially improve therapeutic response to many chemotherapeutic regimes. A new set of usnic acid derivatives with hydrazonothiazole pharmacophore moieties were synthesized and [...] Read more.
Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a promising therapeutic target in cancer therapy. Combination chemotherapy using Tdp1 inhibitors as a component can potentially improve therapeutic response to many chemotherapeutic regimes. A new set of usnic acid derivatives with hydrazonothiazole pharmacophore moieties were synthesized and evaluated as Tdp1 inhibitors. Most of these compounds were found to be potent inhibitors with IC50 values in the low nanomolar range. The activity of the compounds was verified by binding experiments and supported by molecular modeling. The ability of the most effective inhibitors, used at non-toxic concentrations, to sensitize tumors to the anticancer drug topotecan was also demonstrated. The order of administration of the inhibitor and topotecan on their synergistic effect was studied, suggesting that prior or simultaneous introduction of the inhibitor with topotecan is the most effective. Full article
(This article belongs to the Special Issue Facing Novel Challenges in Drug Discovery)
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12 pages, 1997 KiB  
Article
Comparative Study of Aryl O-, C-, and S-Mannopyranosides as Potential Adhesion Inhibitors toward Uropathogenic E. coli FimH
by Leila Mousavifar, Gérard Vergoten, Guillaume Charron and René Roy
Molecules 2019, 24(19), 3566; https://doi.org/10.3390/molecules24193566 - 2 Oct 2019
Cited by 9 | Viewed by 3244
Abstract
A set of three mannopyranoside possessing identical 1,1′-biphenyl glycosidic pharmacophore but different aglyconic atoms were synthesized using either a palladium-catalyzed Heck cross coupling reaction or a metathesis reaction between their corresponding allylic glycoside derivatives. Their X-ray structures, together with their calculated 3D structures, [...] Read more.
A set of three mannopyranoside possessing identical 1,1′-biphenyl glycosidic pharmacophore but different aglyconic atoms were synthesized using either a palladium-catalyzed Heck cross coupling reaction or a metathesis reaction between their corresponding allylic glycoside derivatives. Their X-ray structures, together with their calculated 3D structures, showed strong indicators to explain the observed relative binding abilities against E. coli FimH as measured by a improved surface plasmon resonance (SPR) method. Amongst the O-, C-, and S-linked analogs, the C-linked analog showed the best ability to become a lead candidate as antagonist against uropathogenic E. coli with a Kd of 11.45 nM. Full article
(This article belongs to the Special Issue Facing Novel Challenges in Drug Discovery)
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15 pages, 5271 KiB  
Article
Tracing Potential Covalent Inhibitors of an E3 Ubiquitin Ligase through Target-Focused Modelling
by Imane Bjij, Pritika Ramharack, Shama Khan, Driss Cherqaoui and Mahmoud E. S. Soliman
Molecules 2019, 24(17), 3125; https://doi.org/10.3390/molecules24173125 - 28 Aug 2019
Cited by 4 | Viewed by 3720
Abstract
The Nedd4-1 E3 Ubiquitin ligase has been implicated in multiple disease conditions due its overexpression. Although the enzyme may be targeted both covalently and non-covalently, minimal studies provide effective inhibitors against it. Recently, research has focused on covalent inhibitors based on their characteristic, [...] Read more.
The Nedd4-1 E3 Ubiquitin ligase has been implicated in multiple disease conditions due its overexpression. Although the enzyme may be targeted both covalently and non-covalently, minimal studies provide effective inhibitors against it. Recently, research has focused on covalent inhibitors based on their characteristic, highly-selective warheads and ability to prevent drug resistance. This prompted us to screen for new covalent inhibitors of Nedd4-1 using a combination of computational approaches. However, this task proved challenging due to the limited number of electrophilic moieties available in virtual libraries. Therefore, we opted to divide an existing covalent Nedd4-1 inhibitor into two parts: a non-covalent binding group and a pre-selected α, β-unsaturated ester that forms the covalent linkage with the protein. A non-covalent pharmacophore model was built based on molecular interactions at the binding site. The pharmacophore was then subjected to virtual screening to identify structurally similar hit compounds. Multiple filtrations were implemented prior to selecting four hits, which were validated with a covalent conjugation and later assessed by molecular dynamic simulations. The results showed that, of the four hit molecules, Zinc00937975 exhibited advantageous molecular groups, allowing for favourable interactions with one of the characteristic cysteine residues. Predictive pharmacokinetic analysis further justified the compound as a potential lead molecule, prompting its recommendation for confirmatory biological evaluation. Our inhouse, refined, pharmacophore model approach serves as a robust method that will encourage screening for novel covalent inhibitors in drug discovery. Full article
(This article belongs to the Special Issue Facing Novel Challenges in Drug Discovery)
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11 pages, 3816 KiB  
Article
SAR by Space: Enriching Hit Sets from the Chemical Space
by Franca-Maria Klingler, Marcus Gastreich, Oleksandr O. Grygorenko, Olena Savych, Petro Borysko, Anastasia Griniukova, Kateryna E. Gubina, Christian Lemmen and Yurii S. Moroz
Molecules 2019, 24(17), 3096; https://doi.org/10.3390/molecules24173096 - 26 Aug 2019
Cited by 24 | Viewed by 8338
Abstract
We introduce SAR by Space, a concept to drastically accelerate structure-activity relationship (SAR) elucidation by synthesizing neighboring compounds that originate from vast chemical spaces. The space navigation is accomplished within minutes on affordable standard computer hardware using a tree-based molecule descriptor and dynamic [...] Read more.
We introduce SAR by Space, a concept to drastically accelerate structure-activity relationship (SAR) elucidation by synthesizing neighboring compounds that originate from vast chemical spaces. The space navigation is accomplished within minutes on affordable standard computer hardware using a tree-based molecule descriptor and dynamic programming. Maximizing the synthetic accessibility of the results from the computer is achieved by applying a careful selection of building blocks in combination with suitably chosen reactions; a decade of in-house quality control shows that this is a crucial part in the process. The REAL Space is the largest chemical space of commercially available compounds, counting 11 billion molecules as of today. It was used to mine actives against bromodomain 4 (BRD4). Before synthesis, compounds were docked into the binding site using a scoring function, which incorporates intrinsic desolvation terms, thus avoiding time-consuming simulations. Five micromolar hits have been identified and verified within less than six weeks, including the measurement of IC50 values. We conclude that this procedure is a substantial time-saver, accelerating both ligand and structure-based approaches in hit generation and lead optimization stages. Full article
(This article belongs to the Special Issue Facing Novel Challenges in Drug Discovery)
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10 pages, 1656 KiB  
Article
How Size Matters: Diversity for Fragment Library Design
by Yun Shi and Mark von Itzstein
Molecules 2019, 24(15), 2838; https://doi.org/10.3390/molecules24152838 - 5 Aug 2019
Cited by 29 | Viewed by 7204
Abstract
Fragment-based drug discovery (FBDD) has become a major strategy to derive novel lead candidates for various therapeutic targets, as it promises efficient exploration of chemical space by employing fragment-sized (MW < 300) compounds. One of the first challenges in implementing a FBDD approach [...] Read more.
Fragment-based drug discovery (FBDD) has become a major strategy to derive novel lead candidates for various therapeutic targets, as it promises efficient exploration of chemical space by employing fragment-sized (MW < 300) compounds. One of the first challenges in implementing a FBDD approach is the design of a fragment library, and more specifically, the choice of its size and individual members. A diverse set of fragments is required to maximize the chances of discovering novel hit compounds. However, the exact diversity of a certain collection of fragments remains underdefined, which hinders direct comparisons among different selections of fragments. Based on structural fingerprints, we herein introduced quantitative metrics for the structural diversity of fragment libraries. Structures of commercially available fragments were retrieved from the ZINC database, from which libraries with sizes ranging from 100 to 100,000 compounds were selected. The selected libraries were evaluated and compared quantitatively, resulting in interesting size-diversity relationships. Our results demonstrated that while library size does matter for its diversity, there exists an optimal size for structural diversity. It is also suggested that such quantitative measures can guide the design of diverse fragment libraries under different circumstances. Full article
(This article belongs to the Special Issue Facing Novel Challenges in Drug Discovery)
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Review

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10 pages, 448 KiB  
Review
Unprecedented Potential for Neural Drug Discovery Based on Self-Organizing hiPSC Platforms
by Agustín Cota-Coronado, Jennifer C. Durnall, Néstor Fabián Díaz, Lachlan H. Thompson and N. Emmanuel Díaz-Martínez
Molecules 2020, 25(5), 1150; https://doi.org/10.3390/molecules25051150 - 4 Mar 2020
Cited by 8 | Viewed by 4196
Abstract
Human induced pluripotent stem cells (hiPSCs) have transformed conventional drug discovery pathways in recent years. In particular, recent advances in hiPSC biology, including organoid technologies, have highlighted a new potential for neural drug discovery with clear advantages over the use of primary tissues. [...] Read more.
Human induced pluripotent stem cells (hiPSCs) have transformed conventional drug discovery pathways in recent years. In particular, recent advances in hiPSC biology, including organoid technologies, have highlighted a new potential for neural drug discovery with clear advantages over the use of primary tissues. This is important considering the financial and social burden of neurological health care worldwide, directly impacting the life expectancy of many populations. Patient-derived iPSCs-neurons are invaluable tools for novel drug-screening and precision medicine approaches directly aimed at reducing the burden imposed by the increasing prevalence of neurological disorders in an aging population. 3-Dimensional self-assembled or so-called ‘organoid’ hiPSCs cultures offer key advantages over traditional 2D ones and may well be gamechangers in the drug-discovery quest for neurological disorders in the coming years. Full article
(This article belongs to the Special Issue Facing Novel Challenges in Drug Discovery)
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17 pages, 3790 KiB  
Review
A Novel Prodrug Approach for Central Nervous System-Selective Estrogen Therapy
by Katalin Prokai-Tatrai and Laszlo Prokai
Molecules 2019, 24(22), 4197; https://doi.org/10.3390/molecules24224197 - 19 Nov 2019
Cited by 19 | Viewed by 5118
Abstract
Beneficial effects of estrogens in the central nervous system (CNS) results from the synergistic combination of their well-orchestrated genomic and non-genomic actions, making them potential broad-spectrum neurotherapeutic agents. However, owing to unwanted peripheral hormonal burdens by any currently known non-invasive drug administrations, the [...] Read more.
Beneficial effects of estrogens in the central nervous system (CNS) results from the synergistic combination of their well-orchestrated genomic and non-genomic actions, making them potential broad-spectrum neurotherapeutic agents. However, owing to unwanted peripheral hormonal burdens by any currently known non-invasive drug administrations, the development of estrogens as safe pharmacotherapeutic modalities cannot be realized until they are confined specifically and selectively to the site of action. We have developed small-molecule bioprecursor prodrugs carrying the para-quinol scaffold on the steroidal A-ring that are preferentially metabolized in the CNS to the corresponding estrogens. Here, we give an overview of our discovery of these prodrugs. Selected examples are shown to illustrate that, independently of the route of administrations and duration of treatments, these agents produce high concentration of estrogens only in the CNS without peripheral hormonal liability. 10β,17β-Dihydroxyestra-1,4-dien-3-one (DHED) has been the best-studied representative of this novel type of prodrugs for brain and retina health. Specific applications in preclinical animal models of centrally-regulated and estrogen-responsive human diseases, including neurodegeneration, menopausal symptoms, cognitive decline and depression, are discussed to demonstrate the translational potential of our prodrug approach for CNS-selective and gender-independent estrogen therapy with inherent therapeutic safety. Full article
(This article belongs to the Special Issue Facing Novel Challenges in Drug Discovery)
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