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- Bondarev, Andrey D., et al.
(author)
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Opportunities and challenges for drug discovery in modulating Adhesion G protein-coupled receptor (GPCR) functions
- 2020
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In: Expert Opinion on Drug Discovery. - : TAYLOR & FRANCIS LTD. - 1746-0441 .- 1746-045X. ; 15:11, s. 1291-1307
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Research review (peer-reviewed)abstract
- Introduction: The G protein-coupled receptors (GPCR) superfamily is among the most widely exploited targets for therapeutics, with drugs mainly targeting the Rhodopsin, Glutamate and Secretin family receptors. The receptors of the Adhesion family, however, remain comparatively unexplored in this aspect. This review aims to discuss the druggability of Adhesion GPCRs (aGPCR), highlighting the relevant opportunities and challenges.Areas Covered: In this review, the authors provide a disease-oriented summary of aGPCR involvement in humans and discuss the current status of characterizing therapeutic agents with a focus on new opportunities using low molecular weight substances.Expert opinion: The small molecule antagonist dihydromunduletone and partial agonist 3-alpha-acetoxydihydrodeoxygedunin, along with the endogenous natural ligand synaptamide currently comprise some of the most important discoveries made in an attempt to characterize aGPCR druggability. The small molecule modulators provide important insights regarding the structure-activity relationship and suggest that targeting the tethered peptide agonist results in a nonselective pharmacological action, while synaptamide may be considered a potentially attractive tool to achieve a higher degree of selectivity.
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| 2. |
- Bondarev, Andrey D, et al.
(author)
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Recent developments of HDAC inhibitors : Emerging indications and novel molecules
- 2021
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In: British Journal of Clinical Pharmacology. - : John Wiley & Sons. - 0306-5251 .- 1365-2125. ; 87:12, s. 4577-4597
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Journal article (peer-reviewed)abstract
- The histone deacetylase (HDAC) enzymes, a class of epigenetic regulators, are historically well established as attractive therapeutic targets. During investigation of trends within clinical trials, we have identified a high number of clinical trials involving HDAC inhibitors, prompting us to further evaluate the current status of this class of therapeutic agents. In total, we have identified 32 agents with HDAC-inhibiting properties, of which 29 were found to interact with the HDAC enzymes as their primary therapeutic target. In this review, we provide an overview of the clinical drug development highlighting the recent advances and provide analysis of specific trials and, where applicable, chemical structures. We found haematologic neoplasms continue to represent the majority of clinical indications for this class of drugs; however, it is clear that there is an ongoing trend towards diversification. Therapies for non-oncology indications including HIV infection, muscular dystrophies, inflammatory diseases as well as neurodegenerative diseases such as Alzheimer's disease, frontotemporal dementia and Friedreich's ataxia are achieving promising clinical progress. Combinatory regimens are proving to be useful to improve responsiveness among FDA-approved agents; however, it often results in increased treatment-related toxicities. This analysis suggests that the indication field is broadening through a high number of clinical trials while several fields of preclinical development are also promising.
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| 3. |
- Bondarev, Andrey D., et al.
(author)
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Recent developments of phosphodiesterase inhibitors : Clinical trials, emerging indications and novel molecules
- 2022
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In: Frontiers in Pharmacology. - : Frontiers Media S.A.. - 1663-9812. ; 13
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Research review (peer-reviewed)abstract
- The phosphodiesterase (PDE) enzymes, key regulator of the cyclic nucleotide signal transduction system, are long-established as attractive therapeutic targets. During investigation of trends within clinical trials, we have identified a particularly high number of clinical trials involving PDE inhibitors, prompting us to further evaluate the current status of this class of therapeutic agents. In total, we have identified 87 agents with PDE-inhibiting capacity, of which 85 interact with PDE enzymes as primary target. We provide an overview of the clinical drug development with focus on the current clinical uses, novel molecules and indications, highlighting relevant clinical studies. We found that the bulk of current clinical uses for this class of therapeutic agents are chronic obstructive pulmonary disease (COPD), vascular and cardiovascular disorders and inflammatory skin conditions. In COPD, particularly, PDE inhibitors are characterised by the compliance-limiting adverse reactions. We discuss efforts directed to appropriately adjusting the dose regimens and conducting structure-activity relationship studies to determine the effect of structural features on safety profile. The ongoing development predominantly concentrates on central nervous system diseases, such as schizophrenia, Alzheimer's disease, Parkinson's disease and fragile X syndrome; notable advancements are being also made in mycobacterial infections, HIV and Duchenne muscular dystrophy. Our analysis predicts the diversification of PDE inhibitors' will continue to grow thanks to the molecules in preclinical development and the ongoing research involving drugs in clinical development.
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