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
| Autor: | Todd Macklin, Mark Carlton, Hopkins Maria, Stephen Hitchcock, Hans H Schiffer, Deanna R Collia, Steve Moore, Kikuchi Shota, Nicole Marion English, Mark L. Adams, Murphy Sean, William J. Ray, Jason Green, Jason W. Brown, Holger Monenschein, Huikai Sun, Nicola Brice, Holly Reichard, Nidhi Kaushal |
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| Rok vydání: | 2021 |
| Předmět: |
Parkinson's disease
Pharmacology Catalepsy Medium spiny neuron Indirect pathway of movement 01 natural sciences Receptors G-Protein-Coupled Rats Sprague-Dawley 03 medical and health sciences Structure-Activity Relationship Basal ganglia Drug Discovery medicine Inverse agonist Animals Humans 030304 developmental biology 0303 health sciences Dose-Response Relationship Drug Molecular Structure Chemistry Parkinson Disease medicine.disease 0104 chemical sciences Rats 010404 medicinal & biomolecular chemistry Neuroprotective Agents Dopamine receptor GPR6 Molecular Medicine Female |
| Zdroj: | Journal of medicinal chemistry. 64(14) |
| ISSN: | 1520-4804 |
| Popis: | Parkinson's disease (PD) is a chronic and progressive movement disorder with the urgent unmet need for efficient symptomatic therapies with fewer side effects. GPR6 is an orphan G-protein coupled receptor (GPCR) with highly restricted expression in dopamine receptor D2-type medium spiny neurons (MSNs) of the indirect pathway, a striatal brain circuit which shows aberrant hyperactivity in PD patients. Potent and selective GPR6 inverse agonists (IAG) were developed starting from a low-potency screening hit (EC50 = 43 μM). Herein, we describe the multiple parameter optimization that led to the discovery of multiple nanomolar potent and selective GPR6 IAG, including our clinical compound CVN424. GPR6 IAG reversed haloperidol-induced catalepsy in rats and restored mobility in the bilateral 6-OHDA-lesioned rat PD model demonstrating that inhibition of GPR6 activity in vivo normalizes activity in basal ganglia circuitry and motor behavior. CVN424 is currently in clinical development to treat motor symptoms in Parkinson's disease. |
| Databáze: | OpenAIRE |
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