Solangepras

CAS 2254706-21-1

MF C24H29F2N5O3 MW473.525 g/mol

ETHANONE, 1-(2-(4-(2,4-DIFLUOROPHENOXY)-1-PIPERIDINYL)-7,8-DIHYDRO-3-(((3R)-TETRAHYDRO-3-FURANYL)AMINO)PYRIDO(3,4-B)PYRAZIN-6(5H)-YL)-

1-(2-[4-(2,4-difluorophenoxy)piperidin-1-yl]-3-{[(3R)-oxolan-3-yl]amino}-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one
G protein-coupled receptor 6 (GCPR6) inverse agonist, antiparkinsonian, CVN 424, PHASE 3, Parkinson’s disease

Solangepras (developmental code name CVN-424, also spelled solengepras) is an investigational, orally active small molecule drug currently in Phase 3 clinical trials for the treatment of Parkinson’s disease. Developed by the biotech company Cerevance, it represents a potentially first-in-class non-dopaminergic therapy designed to improve motor control without the debilitating side effects often triggered by traditional dopamine replacements.

Mechanism of Action

Unlike standard Parkinson’s treatments (such as levodopa) that directly target and stimulate dopamine pathways, solangepras utilizes an innovative, highly targeted pathway:

• GPR6 Inverse Agonist: It selectively targets the G protein-coupled receptor 6 (GPR6), an orphan receptor primarily localized in the striatopalidal medium spiny neurons of the basal ganglia.
• Modulating the “Brake” Circuit: In Parkinson’s disease, the indirect brain circuit that inhibits unwanted movement acts as an overactive “brake”. By decreasing intracellular cyclic AMP (cAMP) levels, solangepras reduces this excessive inhibitory signaling.
• Restoring Circuit Balance: It restores balance to the basal ganglia circuit, facilitating better motor function without causing dopamine-related side effects like levodopa-induced dyskinesia (involuntary movements).

Clinical Trial Status

Solangepras is being evaluated across different stages of Parkinson’s disease, shifting focus primarily toward combination therapy:

Clinical Trial / Phase	Treatment Type	Results & Focus
Phase 2 (ASCEND Trial)	Monotherapy (Early, untreated patients)	Missed its primary endpoint. It did not demonstrate superior efficacy alone for early-stage patients, though it showed positive trends in non-motor symptoms.
Phase 2 (NCT04191577)	Adjunctive Therapy (Combination with levodopa)	Successful. Demonstrated a clinically meaningful reduction in daily “OFF time” (periods when standard medication wears off and symptoms return) and increased “ON time” without dyskinesia.
Phase 3 (ARISE Trial)	Adjunctive Therapy	Ongoing. Dosing began late last year to assess efficacy in 330 patients experiencing motor fluctuations, focusing on long-term daily OFF-time reduction.

Chemical & Research Profile

In scientific and laboratory settings, the compound is detailed as follows:

• Chemical Name: 1-[2-[4-(2, 4-difluorophenoxy)piperidin-1-yl]-3-[[(3R)-oxolan-3-yl, amino]-7,8-dihydro-5H-pyrido[3, 4-b, pyrazin-6-yl]ethanone.
• Molecular Formula: C₂₄H₂₉F₂N₅O₃ with a molecular weight of 473.52 g/mol.
• Identifiers: Registered under CAS number 2254706-21-1

• OriginatorCerevance
• ClassAntiparkinsonians; Cyclic ethers; Fluorobenzenes; Furans; Ketones; Phenyl ethers; Piperidines; Pyrazines; Pyridines; Small molecules
• Mechanism of ActionGPR6 protein inhibitors
• Phase IIIParkinson’s disease
• 20 Mar 2026Chemical structure information added.
• 05 Dec 2025Efficacy data from a phase II ASCEND trial in Parkinson’s disease released by Cerevance
• 01 Apr 2025Adverse events and efficacy data from a phase II ASCEND trial in Parkinson’s disease released by Cerevance

Solangepras (INNTooltip International Nonproprietary Name; developmental code name CVN-424), or solengepras (USANTooltip United States Adopted Name), is an inverse agonist of the orphan G protein-coupled receptor 6 (GPR6) which is under development for the treatment of Parkinson’s disease.^[1][2][3][4] It is a small molecule and is taken by mouth.^[1][4] Solangepras produces hyperlocomotion and reverses haloperidol-induced catalepsy in rodents.^[4] It is being developed by Cerevance.^[1][2] As of October 2024, solangepras is in phase 3 clinical trials.^[1][2]

PATENTS

WO 2015/095728 A1 (PCT Application)

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015095728&_cid=P21-MUEWTH-04566-1

[00653] Example 149 (5)-l-(2-(4-(2,4-difluorophenoxy)piperidin-l-yl)-3-(tetrahydrofuran-3-ylamino)-7,8-dihydropyrido[3,4-/?]pyrazin-6(5H)-yl)ethanone

[00654] To a solution of (5)-2-(4-(2,4-difluorophenoxy)piperidin-l-yl)-N-(tetrahydrofuran-3-yl)pyrido[3,4-Z?]pyrazin-3-amine (2.0 g, 4.68 mmol) in dioxane:acetone (50 ml; 1.5: 1) was added Ac₂0 (4.8 mL, 50.9 mmol) and Pd/C (400 mg, 3.76 mmol); then, the reaction was stirred at 60 °C under ¾ atmosphere (345 kPa) for 72 h. The mixture was filtered through a pad of Celite™ and washed with EtOAc. The reaction solution was diluted with EtOAc (50 mL) and poured into sat. aqueous aHC0₃ (50 ml), then washed with brine (2 x 30 mL). The organic layer was dried over Na₂S0₄ and concentrated to give the crude product, which was purified by flash column chromatography to yield the title compound (193.4 mg) as an off-white solid. ^XH NMR (400 MHz, DMSO-i/6) δ ppm 1.88-1.89 (m, 4H), 2.05-2.09 (m, 4H), 2.60-2.90 (m, 4H), 3.30-3.40 (m, 4H), 3.55-3.57 (m, 1H), 3.68-3.74 (m, 2H), 3.85-3.95 (m, 2H), 4.38-4.51 (m, 4H), 5.91 (dd, J= 6.0, 4.4 Hz, 1H), 7.01 (m, 1H), 7.25-7.31 (m, 2H); ESI-MS m/z [M+H]⁺ 474.3.

PAT

US 10,406,157 B2 / US 2018/0360831 A1

https://patentscope.wipo.int/search/en/detail.jsf?docId=US235206887&_cid=P21-MUEX2M-11550-1.

Example 1: (R)-1-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-((tetrahydrofuran-3-yl)amino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one

 To a flask charged with (R)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine (16 g, 37.4 mmol) in HOAc (80 mL) and THF (80 mL) was added acetic anhydride (17.66 mL, 187 mmol) under nitrogen. Palladium on carbon (10%, Aldrich 205699-10G, Lot #MKBZ3284V) (3.19 g, 2.99 mmol) was added under nitrogen. The flask was connected to a hydrogen-filled balloon and was evacuated with house vacuum and refilled with hydrogen eight times. The reaction mixture was stirred under hydrogen for 40 hours and then filtered through a pad of CELITE®, taking care not to let the cake dry out. The flask and filter cake were rinsed with EtOAc (48 mL), methanol (48 mL) and EtOAc (48 mL). The filtrate was concentrated in vacuo to remove THF, EtOAc and methanol (bath temperature ≤40° C.). The solution was diluted with heptane (480 mL) and reconcentrated in vacuo to azetrope off HOAc (bath temperature ≤45° C.). The residue was taken up in iPrOAc (320 mL), washed with 10 wt % aqueous K2CO ₃ (320 mL, 230 mmol) (pH 13 before wash, pH 10 after wash) and brine (240 mL, pH 7 after wash), dried over MgSO ₄, concentrated in vacuo and dried under house vacuum for at least 1 hour to give a light yellow solid (16.71 g). The crude product was taken up in ethanol (84 mL) and was heated in an oil bath with stirring. After the solids were dissolved, the solution was allowed to cool slowly in the oil bath with stirring, during which a precipitate started to form, and the solution became cloudy. The mixture was allowed to cool to ambient temperature in the oil bath and was stirred overnight. Following recrystallization, the white solid was collected by vacuum filtration, rinsed with ice-cold ethanol, and dried under high vacuum to give the title compound as a white solid (13.34 g, 75%). ¹H NMR (500 MHz, DMSO-d ₆) δ ppm 1.81-2.00 (m, 3H), 2.02-2.12 (m, 5H), 2.14-2.24 (m, 1H), 2.60 (t, J=5.61 Hz, 1H), 2.72 (t, J=5.86 Hz, 1H), 2.84-2.96 (m, 2H), 3.26-3.32 (m, 2H), 3.56 (dt, J=8.79, 5.13 Hz, 1H), 3.65-3.78 (m, 3H), 3.81-3.94 (m, 2H), 4.33-4.47 (m, 3H), 4.52 (tt, J=8.18, 4.03 Hz, 1H), 5.91 (dd, J=13.42, 6.10 Hz, 1H), 6.97-7.05 (m, 1H), 7.24-7.36 (m, 2H); ESI-MS m/z [M+H] ⁺ 474; mp 150° C. (DSC peak); chiral purity (via chiral column chromatography)>98% ee.

PAT

WO 2018/209255 / US 10,406,157 B2

PAT

WO 2025/160132

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References

Clinical data
Other names	Solengepras; CVN-424; CVN424
Routes of administration	Oral[1]
Drug class	GPR6 inverse agonist
Identifiers
IUPAC name
CAS Number	2254706-21-1
PubChem CID	137359492
DrugBank	DB18958
ChemSpider	114869317
UNII	XO01711URG
KEGG	D12980
ChEMBL	ChEMBL4778540
Chemical and physical data
Formula	C24H29F2N5O3
Molar mass	473.525 g·mol−1
3D model (JSmol)	Interactive image
SMILES
InChI

1. “Solengepras”. AdisInsight. 21 October 2024. Retrieved 25 February 2025.
2. “Delving into the Latest Updates on CVN-424 with Synapse”. Synapse. 5 February 2025. Retrieved 25 February 2025.
3. Gros P, Garcia LA, Fox SH (2025). “Experimental Therapeutics in Parkinson’s Disease”. Neurologic Clinics. 43 (2): 399–426. doi:10.1016/j.ncl.2024.12.013. PMID 40185528.
4. Brice NL, Schiffer HH, Monenschein H, Mulligan VJ, Page K, Powell J, et al. (June 2021). “Development of CVN424: A Selective and Novel GPR6 Inverse Agonist Effective in Models of Parkinson Disease”. The Journal of Pharmacology and Experimental Therapeutics. 377 (3): 407–416. doi:10.1124/jpet.120.000438. PMID 33795395.

External links

• Solengepras (CVN424) – Cerevance

////////////solangepras, anax labs, G protein-coupled receptor 6 (GCPR6) inverse agonist, antiparkinsonian, CVN 424, PHASE 3, Parkinson’s disease

#solangepras, #anax labs, #G protein-coupled receptor 6 (GCPR6) inverse agonist, #antiparkinsonian, #CVN 424, #PHASE 3, #Parkinson’s disease