Breakthroughs in neuroactive steroid drug discovery

Blanco, Marı́a-Jesús; La, Daniel S.; Coughlin, Quinn; Newman, Caitlin A.; Griffin, Andrew M.; Harrison, Boyd L.; Salituro, Francesco G.

doi:10.1016/j.bmcl.2017.11.043

Cited by 38 publications

(30 citation statements)

References 50 publications

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“…Today, the number and nature of chemical modalities that have led to the appropriate modulation of pathophysiology for therapeutic use have increased remarkably. These range, on one end of the spectrum, from small molecules designed with parameters increasingly beyond those set by the Ro5 [e.g., oxysterols (Blanco et al 2018), cyclic peptides, millamolecular chemistry (millamolecular chemistry refers to macrocycles with a molecular weight between 500 and 1,000 daltons), PROTACs (Churcher 2017)] to molecular entities grouped under the name "biologics," such as antibodies, antibody-drug conjugates, peptides, and oligonucleotides. With so many different chemical modalities having been incorporated into the arsenal of scientists, it behooves drug discovery project teams to secure experimental support, in the way of preponderance of evidence, for the concept that the drug is acting according to the mechanism of action at the core of the biological hypothesis.…”

Section: Resultsmentioning

confidence: 99%

Quality of Research Tools

Doller

Wes

2019

Good Research Practice in Non-Clinical Pharmacology and Biomedicine

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Drug discovery research is a complex undertaking conducted by teams of scientists representing the different areas involved. In addition to a strong familiarity with existing knowledge, key relevant concepts remain unknown as activities start. This is often an accepted risk, mitigated by gaining understanding in real time as the project develops. Chemicals play a role in all biology studies conducted in the context of drug discovery, whether endogenously or exogenously added to the system under study. Furthermore, new knowledge often flourishes at the interface of existing areas of expertise. Due to differences in their training, adding a chemist's perspective to research teams would at least avoid potentially costly mistakes and ideally make any biology research richer. Thus, it would seem natural that one such team member be a chemist. Still, as that may not always be the case, we present some suggestions to minimize the risk of irreproducibility due to chemistry-related issues during biology research supporting drug discovery and make these efforts more robust and impactful. These include discussions on identity and purity, target and species selectivity, and chemical modalities such as orthosteric or allosteric small molecules or antibodies. Given the immense diversity of potential chemical/biological system interactions, we do not intend to provide a foolproof guide to conduct biological experimentation.

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Section: Resultsmentioning

confidence: 99%

Quality of Research Tools

Doller

Wes

2019

Good Research Practice in Non-Clinical Pharmacology and Biomedicine

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“…In addition, neuroactive steroids, independent of their central or peripheral origin, regulate a wide range of key physiological processes in the CNS by regulating gene expression, neuronal excitability and signaling. These data have provided the basis for their neuroprotective, neuroregenerative and neuropsychopharmacological effects that may be pertinent for AD treatment [ 9 , 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Steroids and Alzheimer’s Disease: Changes Associated with Pathology and Therapeutic Potential

Akwa

2020

IJMS

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Alzheimer’s disease (AD) is a multifactorial age-related neurodegenerative disease that today has no effective treatment to prevent or slow its progression. Neuroactive steroids, including neurosteroids and sex steroids, have attracted attention as potential suitable candidates to alleviate AD pathology. Accumulating evidence shows that they exhibit pleiotropic neuroprotective properties that are relevant for AD. This review focuses on the relationship between selected neuroactive steroids and the main aspects of AD disease, pointing out contributions and gaps with reference to sex differences. We take into account the regulation of brain steroid concentrations associated with human AD pathology. Consideration is given to preclinical studies in AD models providing current knowledge on the neuroprotection offered by neuroactive (neuro)steroids on major AD pathogenic factors, such as amyloid-β (Aβ) and tau pathology, mitochondrial impairment, neuroinflammation, neurogenesis and memory loss. Stimulating endogenous steroid production opens a new steroid-based strategy to potentially overcome AD pathology. This article is part of a Special Issue entitled Steroids and the Nervous System.

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“…Steroids are an important class of both natural and synthetic products exhibiting various biological activities [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. In the past decades, great efforts were made to accomplish further modification to synthesize structurally new and biologically interesting compounds [ 12 , 13 , 14 , 15 , 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Novel d-Annulated Pentacyclic Steroids: Regioselective Synthesis and Biological Evaluation in Breast Cancer Cells

Vorontsova

Yadykov

Scherbakov³

et al. 2020

Molecules

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The acid-catalyzed cyclization of benzylidenes based on 16-dehydropregnenolone acetate (16-DPA) was studied. It was found that these compounds readily undergo regioselective interrupted Nazarov cyclization with trapping chloride ion and an efficient method of the synthesis of d-annulated pentacyclic steroids based on this reaction was proposed. The structures of the synthesized pentacyclic steroids were determined by NMR and X-ray diffraction. It was found that the reaction affords a single diastereomer, but the latter can crystallize as two conformers depending on the structure. Antiproliferative activity of synthesized compounds was evaluated against two breast cancer cell lines: MCF-7 and MDA-MB-231. All tested compounds showed relatively high antiproliferative activity. The synthetic potential of the protocol developed was illustrated by the gram-scale experiment.

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Breakthroughs in neuroactive steroid drug discovery

Cited by 38 publications

References 50 publications

Quality of Research Tools

Quality of Research Tools

Steroids and Alzheimer’s Disease: Changes Associated with Pathology and Therapeutic Potential

Novel d-Annulated Pentacyclic Steroids: Regioselective Synthesis and Biological Evaluation in Breast Cancer Cells

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