First-Time Disclosure of CVN424, a Potent and Selective GPR6 Inverse Agonist for the Treatment of Parkinson’s Disease: Discovery, Pharmacological Validation, and Identification of a Clinical Candidate

Sun, Huikai; Monenschein, Holger; Schiffer, Hans H.; Reichard, H; Kikuchi, Shota; Hopkins, Maria; Macklin, Todd K; Hitchcock, Stephen; Adams, Mark E.; Green, Jason; Brown, Jason W.; Murphy, Sean T.; Kaushal, Nidhi; Collia, Deanna; Moore, Samuel K.; Ray, William J.; English, Nicole M.; Carlton, Mark; Brice, Nicola

doi:10.1021/acs.jmedchem.0c02081

Cited by 23 publications

(10 citation statements)

References 37 publications

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“…To reduce RNA degradation all nuclei samples were sorted at 4 °C and stored at −80 °C, before being processed for RNA extraction. RNA quality was assessed as previously described ( Sun et al, 2021 ). Gene expression quantification was performed with htseq-count v 0.6.1p1 using a custom annotation file to be able to quantify reads in both exons and introns of RefSeq genes.…”

Section: Methodsmentioning

confidence: 99%

Characterisation of C101248: A novel selective THIK-1 channel inhibitor for the modulation of microglial NLRP3-inflammasome

et al. 2023

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Section: Methodsmentioning

confidence: 99%

Characterisation of C101248: A novel selective THIK-1 channel inhibitor for the modulation of microglial NLRP3-inflammasome

et al. 2023

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“…It has been hypothesized that antagonism of this receptor provides a compensatory inhibition to the hyperactivity of the indirect pathway resulting from dopamine depletion. Preclinical studies using rat models have shown that CVN424 restores the normal basal ganglia circuitry and improves motor behavior in vivo [ 166 ]. A Phase 2 trial involving 135 PD patients with motor fluctuations is currently underway to evaluate the compound’s safety and efficacy (NCT04191577) [ 167 ].…”

Section: Motor Fluctuationsmentioning

confidence: 99%

Newly Approved and Investigational Drugs for Motor Symptom Control in Parkinson's Disease

Luca

Reyes

Fox

2022

Drugs

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Motor symptoms are a core feature of Parkinson’s disease (PD) and cause a significant burden on patients’ quality of life. Oral levodopa is still the most effective treatment, however, the motor benefits are countered by inherent pharmacologic limitations of the drug. Additionally, with disease progression, chronic levodopa leads to the appearance of motor complications including motor fluctuations and dyskinesia. Furthermore, several motor abnormalities of posture, balance, and gait may become less responsive to levodopa. With these unmet needs and our evolving understanding of the neuroanatomic and pathophysiologic underpinnings of PD, several advances have been made in defining new therapies for motor symptoms. These include newer levodopa formulations and drug delivery systems, refinements in adjunctive medications, and non-dopaminergic treatment strategies. Although some are in early stages of development, these novel treatments potentially widen the available options for the management of motor symptoms allowing clinicians to provide an individually tailored care for PD patients. Here, we review the existing and emerging interventions for PD with focus on newly approved and investigational drugs for motor symptoms, motor fluctuations, dyskinesia, and balance and gait dysfunction.

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“…GPR6 is a constitutively highly active G-protein coupled receptor 33,34 . This receptor is mainly expressed in mammalian brain, specifically striatum and hypothalamus, with very low expression at peripheral level.…”

Section: Resultsmentioning

confidence: 99%

Illuminating the Druggable Genome through Patent Bioactivity Data

Leach

Magariños

Gaulton

et al. 2022

Preprint

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The patent literature is a potentially valuable source of bioactivity data. The SureChEMBL database (https://www.surechembl.org/) is a publicly available large-scale resource that contains compounds extracted on a daily basis from the full text, images and attachments of patent documents, through an automated text and image-mining pipeline. In this paper we describe a process to prioritise 3.7 million life science relevant patents obtained from SureChEMBL, according to how likely they were to contain bioactivity data for potent small molecules on less-studied targets, according to the classification developed by the Illuminating the Druggable Genome (IDG) project. The overall goal was to select a smaller number of patents that could be manually curated and incorporated into the ChEMBL database. We describe the approach taken, the results obtained, and provide some illustrative examples.

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First-Time Disclosure of CVN424, a Potent and Selective GPR6 Inverse Agonist for the Treatment of Parkinson’s Disease: Discovery, Pharmacological Validation, and Identification of a Clinical Candidate

Cited by 23 publications

References 37 publications

Characterisation of C101248: A novel selective THIK-1 channel inhibitor for the modulation of microglial NLRP3-inflammasome

Characterisation of C101248: A novel selective THIK-1 channel inhibitor for the modulation of microglial NLRP3-inflammasome

Newly Approved and Investigational Drugs for Motor Symptom Control in Parkinson's Disease

Illuminating the Druggable Genome through Patent Bioactivity Data

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