Lirafugratinib

 

Lirafugratinib

• CAS No.:2549174-42-5
• Formula:C₂₈H₂₄FN₇O₂
• Molecular Weight:509.53

FDA 2026, APPROVALS 2026, Lyrfigtu, RLY-4008, RLY 4008, 23SEPT2026

N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-
d]pyrimidin-6-yl)phenyl)methacrylamide (lirafugratinib)

To adults with previously treated unresectable, locally advanced or metastatic cholangiocarcinoma harboring a fibroblast growth factor receptor 2 gene fusion or other rearrangement

Lirafugratinib (RLY-4008) is an orally active, irreversible and highly selective FGFR2 inhibitor with an IC₅₀ of 3 nM. Lirafugratinib covalently binds to Cys491. Lirafugratinib targets FGFR2 primary alterations and resistance mutations and induces tumor regression while sparing other FGFRs.

Lirafugratinib (Lyrfigtu) received FDA approval on September 23, 2026, for adults with previously treated, unresectable or metastatic cholangiocarcinoma involving FGFR2 gene fusions or rearrangements.

Overview & Mechanism

• Drug Class: An oral, selective, and irreversible FGFR2 small-molecule inhibitor.
• Developer/Marketed By: Developed by Relay Therapeutics and commercialized globally by Elevar Therapeutics.
• How it Works: Covalently targets the FGFR2 kinase domain to inhibit tumor-driving signaling while sparing other FGFR proteins to limit off-target effects.

Efficacy

• Clinical Trial: Assessed in the phase 1/2 REFOCUS trial (NCT04526106) involving 116 previously treated, FGFR-inhibitor-naive patients.
• Key Metrics: Demonstrated an objective response rate of 46%, a median duration of response of 11.8 months, and a median progression-free survival of 11.3 months.

Dosing & Administration

• Recommended Dose: 70 mg orally once daily on a continuous basis until disease progression or unacceptable toxicity.

Safety & Warnings

• Common Adverse Events: Hand-foot syndrome, stomatitis, nail issues, and ocular/retinal toxicities.
• Special Warnings: Includes precautions for ocular toxicity, hyperphosphatemia, soft tissue mineralization, and embryo-fetal risks

PAPER

https://pmc.ncbi.nlm.nih.gov/articles/PMC10861881

SEE https://pmc.ncbi.nlm.nih.gov/articles/instance/10861881/bin/pnas.2317756121.sapp.pdf

N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7Hpyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide (lirafugratinib)

5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A round bottomed flask was charged with 5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (10.0 g,
47.16 mmol), Cs2CO3 (22.99 g, 70.75 mmol), DMF (120 mL) and a stirbar. Iodomethane (8.03 g,
56.59 mmol) was added, and the solution was stirred for 1 h at room temperature. The reaction mixture was diluted with H2O (300 mL), and the aqueous phase was extracted with ethyl acetate
(300 mL) three times. The combined organic layers were washed with saturated brines, dried
over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude material was
purified by HPLC. Concentration in vacuo resulted in 5-bromo-7-methyl-7H-pyrrolo[2,3-
d]pyrimidin-4-amine (5 g, 47.1 % ) as an off-white solid.

5-bromo-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A round bottomed flask was charged with 5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-
amine (5 g, 22.12 mmol), DCM (50 mL) and TFA (2 mL) and a stirbar. 1-iodopyrrolidine-2,5-
dione (5.97 g, 26.54 mmol) was added, and the solution was stirred for 2 h at room temperature.
The reaction mixture was diluted with Na2SO3 solution (200 mL), and the aqueous phase was
extracted with DCM (200 mL) three times. The combined organic layers were washed with
saturated brines, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting
crude material was purified by HPLC. Concentration in vacuo resulted in 5-bromo-6-iodo-7-
methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (4 g, 51.3 %) as a yellow solid.

tert-butyl (4-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)carbamate

A resealable reaction vial was charged with 5-bromo-6-iodo-7-methyl-7H-pyrrolo[2,3-
d]pyrimidin-4-amine (4 g, 11.36 mmol), tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)phenyl)carbamate (4.35 g, 13.63 mmol), Pd(dppf)Cl2 (994.16 mg, 1.36 mmol), K3PO4 (7.22
g, 34.08 mmol), DMF (50 mL), H2O (6.25 mL) and a stir bar before being evacuated and purged
with nitrogen three times. The mixture was stirred for 2 h at 90 °C. The reaction mixture was
diluted with H2O (300 mL), and the aqueous phase was extracted with ethyl acetate (300 mL)
three times. The combined organic layers were washed with brines, dried over sodium sulfate,
filtered, and concentrated in vacuo. The resulting crude material was purified by silica gel
chromatography (eluting with MeOH/DCM = 1/40). Concentration in vacuo resulted in tert-butyl
(4-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)carbamate (3 g, 63.4%)
as a yellow solid.

6-(4-aminophenyl)-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A round bottomed flask was charged with tert-butyl (4-(4-amino-5-bromo-7-methyl-7Hpyrrolo[2,3-d]pyrimidin-6-yl)phenyl)carbamate (3 g, 7.19 mmol), DCM (50 mL) and TFA (12.5mL) and a stirbar. The solution was stirred for 1 h at room temperature. The reaction mixture
was diluted with H2O (100 mL), and the aqueous phase was extracted with DCM (50 mL) three
times. The pH of aqueous phase was adjusted to 7~8, then the aqueous phase was extracted with
DCM (100 mL) three times. The combined organic layers were washed with saturated brines,
dried over sodium sulfate, filtered, and concentrated in vacuo resulted in 6-(4-aminophenyl)-5-
bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (2.1 g, 92.1%) as a yellow solid.

N-(4-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide

A resealable reaction vial was charged with 6-(4-aminophenyl)-5-bromo-7-methyl-7Hpyrrolo[2,3-d]pyrimidin-4-amine (2.1 g, 6.62 mmol), pyridine (785 mg, 9.93 mmol), DCM (100
mL) and a stir bar before being evacuated and purged with nitrogen three times. Methacryloyl
chloride (757.3 mg, 7.28 mmol) was added slowly at 0 oC. Then the mixture was stirred for 2 h
at room temperature. The reaction mixture was diluted with H2O (100 mL), and the aqueous
phase was extracted with DCM (100 mL) three times. The combined organic layers were washed
with brines, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude
material was purified by silica gel chromatography (eluting with MeOH/DCM=1/40).
Concentration in vacuo resulted in N-(4-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-
d]pyrimidin-6-yl)phenyl)methacrylamide (1.8 g, 70.5%) as an off-white solid.

2-(4-bromo-2-fluorophenoxy)-4-methylpyrimidine

A round bottomed flask was charged with 4-bromo-2-fluorophenol (1.0 g, 5.24 mmol), 2-fluoro4-methylpyrimidine (704 mg, 6.28 mmol), Cs2CO3 (5.12 g, 15.7 mmol) and a stirbar. DMF (20
mL) was added, and the solution was stirred for 1 h at 100 oC. The reaction mixture was diluted
with H2O (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL) three
times. The combined organic layers were washed with saturated brines, dried over sodium
sulfate, filtered, and concentrated in vacuo. The resulting crude material was purified by HPLC.
Concentration in vacuo resulted in 2-(4-bromo-2-fluorophenoxy)-4-methylpyrimidine (1.48 g,
99.8 %) as an off-white amorphous solid.

2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methylpyrimidine

A solution/mixture of 2-(4-bromo-2-fluorophenoxy)-4-methylpyrimidine (500.00 mg, 1.77
mmol), bis(pinacolato)diboron (672.75 mg, 2.65 mmol), KOAc (520 mg, 5.3 mmol) and
Pd(dppf)Cl2 (129.4 mg, 0.177 mmol) in DMF (10 mL) was stirred for 2 h at 80 oC under nitrogen
atmosphere. The resulting mixture was diluted with water and extracted with EA. The combined
organic layers were washed with brines, dried over anhydrous Na2SO4. After filtration, the
filtrate was concentrated under reduced pressure. The residue was purified by HPLC.
Concentration in vacuo resulted in 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)phenoxy)-4-methylpyrimidine (430 mg, 73.7%) as a yellow solid.

2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methylpyrimidine

A resealable reaction vial was charged with N-(4-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-
d]pyrimidin-6-yl)phenyl)methacrylamide (100 mg, 0.259 mmol), 2-(2-fluoro-4-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methylpyrimidine (102.6 mg, 0.310 mmol),
Pd(DtBPF)Cl2 (16.9 mg, 0.026 mmol), CsF (118 mg, 0.776 mmol), DMF (2 mL), H2O (0.25
mL) and a stir bar before being evacuated and purged with nitrogen three times. The mixture was
stirred for 1 h at 90 °C. The reaction mixture was diluted with H2O (10 mL), and the aqueousphase was extracted with DCM (10 mL) three times. The combined organic layers were washed
with brines, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude
material was purified by Pre-HPLC (Column: XBridge Prep C18 OBD Column, 19*150 mm,
5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25
mL/min; Gradient: 25% B to 50% B in 7 min, 50% B; Wave Length: 254/220 nm; RT1(min):
6.5). Concentration in vacuo resulted in N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-
yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide ( 27.2 mg,
20.6%) as an off-white solid. LC/MS(BAS1): [M+H]+= 510.20; tR =1.405 min. 1H NMR (400
MHz, DMSO-d6) δ 9.92 (s, 1H), 8.47 (d, J = 5.0 Hz, 1H), 8.21 (s, 1H), 7.79 – 7.72 (m, 2H), 7.38
– 7.28 (m, 3H), 7.22 – 7.14 (m, 2H), 7.10 (dd, J = 8.1, 2.1 Hz, 1H), 5.98 (s, 2H), 5.80 (s, 1H),
5.54 (d, J = 1.7 Hz, 1H), 3.59 (s, 3H), 2.42 (s, 3H), 1.95 (d, J = 1.2 Hz, 3H).

PAT

WIPO Patent Publication: WO2020231990A1 (and related family filings)

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020231990&_cid=P20-MUHRQT-01820-1

PAT

United States Patents: US11780845

PAT

US20230192709

https://patentscope.wipo.int/search/en/detail.jsf?docId=US399951539&_cid=P20-MUHRKD-96615-1

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References

[1]. Vivek Subbiah, et al. RLY-4008, the First Highly Selective FGFR2 Inhibitor with Activity across FGFR2 Alterations and Resistance Mutations. Cancer Discov. 2023 Sep 6;13(9):2012-2031. [Content Brief]

/////////lirafugratinib, anax labs, FDA 2026, APPROVALS 2026, Lyrfigtu, RLY-4008, RLY 4008, 23SEPT2026, CANCER

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Solangepras

 

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

Soclenicant

 

Soclenicant

CAS 1020634-41-6

MFC24H26N4O3 MW418.5 g/mol

6-(2,3-dihydro-1H-inden-2-ylamino)-1-ethyl-3-(morpholine-4-carbonyl)-1,8-naphthyridin-4-one

6-[(2,3-dihydro-1H-inden-2-yl)amino]-1-ethyl-3-(morpholine4-carbonyl)-1,8-naphthyridin-4(1H)-one
nicotinic acetylcholine receptor negative allosteric, modulator, anxiolytic, BNC210, IW-2143, BNC 210, IW 2143, QP49AY37OY

BNC-210 is under investigation in clinical trial NCT04951076 (A Phase 2b Study of BNC210 Tablet Formulation in Adults With Post-traumatic Stress Disorder (PTSD)).

Soclenicant (also known by its developmental code names BNC210 and IW-2143) is an investigational, orally active small-molecule drug developed to treat anxiety and stressor-related disorders. It is chemically classified as a synthetic heterocyclic compound based on a 1,8-naphthyridin-4-one scaffold.

Unlike traditional anxiety medications like benzodiazepines, it is designed to provide targeted relief without causing side effects like sedation, motor impairment, memory issues, or physical dependence.

Mechanism of Action

Soclenicant functions as a highly selective negative allosteric modulator (NAM) of the α7-nicotinic acetylcholine receptor (α₇ nAChR).

• It works by tuning down the electric currents induced by neurotransmitters like acetylcholine and nicotine specifically at this receptor subtype.
• In preclinical rodent models, it demonstrated strong acute anxiolytic (anti-anxiety), anti-stress, and antidepressant-like behaviors.

Clinical Development Status

The drug was originally engineered by Bionomics and saw collaborative development alongside entities like Ironwood Pharmaceuticals. Bionomics was acquired by Neuphoria Therapeutics in late 2024.

However, the drug's clinical pipeline faced a massive setback:

• Social Anxiety Disorder (SAD) Flop: In late 2025, a Phase 3 clinical trial evaluating a single 225-mg dose of soclenicant for the acute treatment of social anxiety disorder failed to meet its primary endpoint. It showed no statistically significant improvement in patient distress levels during a public speaking challenge compared to a placebo.
• Current Status: Following the Phase 3 failure, Neuphoria Therapeutics discontinued the social anxiety program and triggered a strategic corporate review. While it has historically been granted FDA Fast Track designation for generalized anxiety disorder (GAD) and explored for Post-Traumatic Stress Disorder (PTSD), the future development pipeline remains uncertain

Soclenicant (INNTooltip International Nonproprietary Name),^[3] also known by its developmental code names BNC210 and IW-2143, is an antinicotinic agent which is under development for the treatment of anxiety disorders such as social phobia and generalized anxiety disorder, as well as for treatment of agitation, post-traumatic stress disorder (PTSD), and depressive disorders.^[1][4][5] It is taken by mouth.^[4]

The drug acts as a highly selective negative allosteric modulator (NAM) of the α₇-nicotinic acetylcholine receptor (α₇-nAChR).^[1][6][4][5] It produces anxiolytic-, anti-stress-, and antidepressant-like effects without causing sedation, memory or motor impairment, or physical dependence in rodents.^[6] Chemically, soclenicant is a synthetic heterocyclic small-molecule compound based on a 1,8-naphthyridin-4-one scaffold, bearing amide and amine functionalities.^[7]

Soclenicant is being developed by Bionomics.^[4] It has also been developed by Ironwood Pharmaceuticals and EmpathBio.^[4][5] Bionomics was acquired by Neuphoria Therapeutics in December 2024.^[4] As of December 2024, soclenicant is in phase 3 clinical trials for anxiety disorders, phase 2 trials for agitation and PTSD, and no recent development has been reported for depressive disorders.^[4][5] The drug received Fast Track designation from the United States Food and Drug Administration (FDA) in 2019.^[8] It was first described in the literature, in a conference abstract, by 2007.^[2]

• Efficacy of BNC210 in Acute, As-needed Treatment of Anxiety in Social Anxiety Disorder - 1CTID:NCT06510504Phase:Phase 3Status:CompletedDate:2026-05-19
• A Phase 2 Study of BNC210 for the Acute Treatment of Social Anxiety DisorderCTID:NCT05193409Phase:Phase 2Status:CompletedDate:2025-03-18
• A Phase 2b Study of BNC210 Tablet Formulation in Adults With Post-Traumatic Stress Disorder (PTSD)CTID:NCT04951076Phase:Phase 2Status:CompletedDate:2025-02-06
• Phase II Study of BNC210 in PTSDCTID:NCT02933606Phase:Phase 2Status:CompletedDate:2023-02-27
• A Study of BNC210 in Elderly Patients With AgitationCTID:NCT03548194Phase:Phase 2Status:CompletedDate:2020-07-09

SYNTHETIC

• The Pathway to Proof‐of‐Concept for BNC210, a Negative Allosteric Modulator of the Alpha‐7 Nicotinic Acetylcholine Receptor (nAChR), for Treatment of Psychiatric DiseasePublication Name:Clinical Pharmacology in Drug DevelopmentPublication Date:2025-09-27PMCID:PMC12856972PMID:41014090DOI:10.1002/cpdd.1609
• BNC210, a negative allosteric modulator of the alpha 7 nicotinic acetylcholine receptor, demonstrates anxiolytic- and antidepressant-like effects in rodentsPublication Name:NeuropharmacologyPublication Date:2024-03-15PMID:38185416DOI:10.1016/j.neuropharm.2024.109836
• BNC210: an investigational α7-nicotinic acetylcholine receptor modulator for the treatment of anxiety disordersPublication Name:Expert Opinion on Investigational DrugsPublication Date:2023-03-20PMID:36927202DOI:10.1080/13543784.2023.2192922
• Cholinergic Modulation of Disorder-Relevant Neural Circuits in Generalized Anxiety DisorderPublication Name:Biological PsychiatryPublication Date:2020-05-15PMCID:PMC7198974PMID:32107005DOI:10.1016/j.biopsych.2019.12.013

INTERMEDIATES

PAT

WO2012151640

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2012151640&_cid=P11-MUC1WO-96887-1

N-1

1-Ethyl-6-(indan-2-ylamino)-4-oxo-1,8-naphthyridine-3-cal-boxylic acid:

Ethanol (42.0 L) was added to reactor at 25-30 °C, followed by ethyl 1 -ethyl-6-(indan-2-ylamino)-4-oxo- 1 ,8-naphthyridine-3-carboxylate (4.20 kg) with stirring. Aqueous sodium hydroxide solution (prepared by dissolving 3.4 kg of sodium hydroxide into 42.0 L of water) was added to reaction mixture at 25-30 °C and reactor temperature was raised to 50-55 °C. The reaction mixture was stirred at 50-55 °C for 2 h and reaction progress was monitored by TLC. After completion of hydrolysis (~3 h), the reaction mass was cooled to 25-30 °C and pH was adjusted to 5-6 by addition of citric acid solution (prepared by dissolving 5.2 kg of citric acid in 47.0 L of water). The reaction mass was stirred for 20-25 minutes at 25-30 °C and filtered, the solid mass was washed with water (42.0 L) and acetone (21 .0 L). The material was transferred to drying trays and dried with hot-air dryer at 70-75 °C until the water content decreased to 1 .0%, yielding the desired compound (90%) as a solid. Ή NMR (DMSO-d6, 500MHz): 1.40(3H, t, J = 7.0Hz), 2.86-2.90(2H, m), 3.37-3.41 (2H, m), 4.38(1 H, d, J = 5.5 Hz), 4.62(2H_? q, J = 7.0Hz), 7.06( 1 H, d, J = 6.0Hz), 7.17-7.18(2H. m), 7.26-7.27(2H, m), 7.60(1 H, d, J = 2.5 Hz), 8.52(1 H, d, J =2.0 Hz), 9.00 (1 H, s), 15.30(1 H, s). ¹³C NMR (DMSO-d6, 125MHz): 15.19, 46.92, 52.92, 107.12, 109.42, 121.58, 124.63, 126.41 , 140.1 1 , 141.12, 143.33, 143.43, 145.93, 166.12, 177.53.

FINAL

6-(2 ,3-Dihydro-1H-inden-2-ylamino)-1-ethyl-3-(morpholin-4-ylcarbonyl)-1,8-naphthyridin-4(1H)-one

Step 1 : 160.0 L of dichloromethane (water content should be no more than 0.1%), 1 -ethyl-6-(indan-2-ylamino)-4-oxo-l ,8-naphthyridine-3-carboxylic acid (4.0 kg) and triethylamine (3.5 kg) were sequentially added to reactor at 25-30°C under nitrogen atmosphere and the reaction mixture was cooled to 10-15 °C. Pivaloyl chloride (4.1 kg) was slowly added to reaction mixture keeping the reaction temperature at 10-15°C. Then, the reaction temperature was raised to 25-30 °C and stirred. The reaction progress was monitored by TLC for disappearance of starting material. After completion of reaction (3-4 h), the reaction mixture was again cooled to 15-20 °C and morpholine (6.0 kg) was added with stirring, keeping the reaction temperature at 1 5-20 °C. N,N-Dimethyl-4-aminopyridine ( 194 g) and DMF (2.0 L) were added to the reaction mixture at 15-20 °C and heated to reflux. The reaction progress was monitored by TLC for the disappearance of intermediate pivaloyl ester and found to be complete within 12-13 h. The reaction mixture was cooled to 15-20 °C and then quenched by addition of aqueous sodium bicarbonate solution (prepared by dissolving 5.6 kg of sodium bicarbonate in 56.0 L of water) with stirring. The organic layer was separated and washed with aqueous sodium chloride solution (prepared by dissolving 23.0 kg of sodium chloride in 57.0 L of water). The organic layer was separated and dried by stirring with anhydrous sodium sulphate (4.0 kg). The organic layer was filtered through a Nutsche filter and the sodium sulphate was washed with dichloromethane. The filtrate was transferred into a flask and evaporated under vacuum below 40 °C. The resulting material in the flask was cooled to 25-30 °C and suspended in diethyl ether (40.0 L). The solid separated was filtered using a Nutsche filter and washed with diethyl ether (8.0 L) and the isolated wet solid was dissolved in dichloromethane (20.0 L). The solution (10.0 L) was then filtered through a silica gel plug (10.0 kg) with dichloromethane (36.0 L), followed by 10 L of 10% methanol in dichloromethane. The silica gel filter was dried under vacuum. Similarly, the remaining portion of solution ( 10.0 L) was filtered through another silica gel plug (10.0 kg). The combined filtrate was evaporated under vacuum below 40 °C and then residual solid was suspended in ethyl acetate (20.0 L) with stirring at 25-30 °C. The solid separated was filtered through Nutsche filter and washed with ethyl acetate (4.0 L). The filter was dried under vacuum and then material was transferred to drying trays and dried at 40-45 °C. Yield (2.36 Kg). ¹H NMR (DMSO-d6, 500MHz): 1.49 (3H, t, J = 7.2Hz), 2.91 (2H, dd, J = 3.5Hz, 16.0 Hz), 3.42-3.47(4H, m), 3.80(6H, s), 4.25-4.26(1H, bd), 4.40-4.48(3H, m), 7.20-7.25(4H, m),

7.82(1H, d, J = 3.0Hz), 8.09 (1H, s), 8.18(1 H, d, J = 3.0Hz). ¹³C NMR (CDCl₃, 150MHz): 15.27, 39.87, 43.05, 46.66, 48.09, 53.93, 66.80, 67.40, 1 13.27, 1 16.71 , 123.22, 124.92, 126.78, 140.87, 141 .46, 141.83, 141.90, 143.84, 166.27, 173.38.

PAT

WO2014138772

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014138772&_cid=P11-MUC1WO-96887-2

United States Patent Number 8,293,737, the entirety of which is incorporated herein by reference, describes certain 1,8-naphthyridin-4(1H)-one compounds which are useful as anxiolytic agents. Such compounds include 1-ethyl-6-(indan-2-ylamino)-3-(morphoIine-4-carbonyl)-1 ,8-naphthyridin-4-one (compound 1).

PAT

• Novel anxiolytic compoundsPublication Number:EP-2540722-A1Priority Date:2006-10-16
• Novel anxiolytic compoundsPublication Number:WO-2008046135-A1Priority Date:2006-10-16
• Novel anxiolytic compoundsPublication Number:EP-2540722-B1Priority Date:2006-10-16Grant Date:2016-06-08
• Anxiolytic compoundsPublication Number:US-10954231-B2Priority Date:2006-10-16Grant Date:2021-03-23
• Anxiolytic compoundsPublication Number:US-10233181-B2Priority Date:2006-10-16Grant Date:2019-03-19
• Novel anxiolytic compoundsPublication Number:US-2013012509-A1Priority Date:2006-10-16
• Novel anxiolytic compoundsPublication Number:US-2018105524-A1Priority Date:2006-10-16
• Novel anxiolytic compoundsPublication Number:US-2017183347-A1Priority Date:2006-10-16
• Anxiolytic compoundsPublication Number:US-8906912-B2Priority Date:2006-10-16Grant Date:2014-12-09

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References

1.  Hampsey E, Perkins A, Young AH (April 2023). "BNC210: an investigational α7-nicotinic acetylcholine receptor modulator for the treatment of anxiety disorders". Expert Opin Investig Drugs. 32 (4): 277–282. doi:10.1080/13543784.2023.2192922. PMID 36927202.
2. Andriambeloson, E., Wagner, S., Huyard, B., Sleebs, B., Quasi, N., Bui, C., ... & Street, I. (2007, September). BNC210: A Novel Compound with Potent Anxiolytic Activity. In Behavioral Pharmacology (Vol. 18, pp. S16–S16). https://neurofit.com/im-posters/2008-ebps-bnc210.pdf
3. https://cdn.who.int/media/docs/default-source/international-nonproprietary-names-(inn)/pl132.pdf#page=198 soclenicantum soclenicant 6-[(2,3-dihydro-1H-inden-2-yl)amino]-1-ethyl-3-(morpholine4-carbonyl)-1,8-naphthyridin-4(1H)-one nicotinic acetylcholine receptor negative allosteric modulator, anxiolytic
4. "BNC 210". AdisInsight. 30 December 2024. Retrieved 22 February 2025.
5. "Delving into the Latest Updates on BNC-210 with Synapse". Synapse. 23 January 2025. Retrieved 22 February 2025.
6. O'Connor SM, Sleebs BE, Street IP, Flynn BL, Baell JB, Coles C, Quazi N, Paul D, Poiraud E, Huyard B, Wagner S, Andriambeloson E, de Souza EB (March 2024). "BNC210, a negative allosteric modulator of the alpha 7 nicotinic acetylcholine receptor, demonstrates anxiolytic- and antidepressant-like effects in rodents". Neuropharmacology. 246 109836. doi:10.1016/j.neuropharm.2024.109836. hdl:11343/348285. PMID 38185416.
7. "CID 24772165". PubChem. Retrieved 5 January 2026.
8. Bionomics Limited Press Release (2019-11-04). "Bionomics Announces Fast Track Designation Granted by U.S. FDA to BNC210 Development Program for the Treatment of PTSD". BusinessWire. Retrieved 2020-09-09.

Clinical data
Other names	BNC210; BNC-210; IW2143; IW-2143
Routes of administration	Oral
Drug class	α7-Nicotinic acetylcholine receptor negative allosteric modulator
ATC code	None
Legal status
Legal status	Investigational
Pharmacokinetic data
Bioavailability	69.4% (rat)[1][2]
Protein binding	70–88%[1][2]
Elimination half-life	6.2 hours (rat)[1][2]
Identifiers
IUPAC name
CAS Number	1020634-41-6
PubChem CID	24772165
UNII	QP49AY37OY
KEGG	D13360
Chemical and physical data
Formula	C24H26N4O3
Molar mass	418.497 g·mol−1
3D model (JSmol)	Interactive image
SMILES
InChI

//////soclenicant, anax labs, nicotinic acetylcholine receptor negative allosteric, modulator, anxiolytic, BNC210, IW-2143, BNC 210, IW 2143, QP49AY37OY

#soclenicant, #anax labs, #nicotinic acetylcholine receptor negative allosteric, #modulator, #anxiolytic, #BNC210, #IW-2143, #BNC 210, #IW 2143, #QP49AY37OY