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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
#lirafugratinib, #anax labs, #FDA 2026, #APPROVALS 2026, #Lyrfigtu, #RLY-4008, #RLY 4008, #23SEPT2026, #CANCER
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 | |
- “Solengepras”. AdisInsight. 21 October 2024. Retrieved 25 February 2025.
- “Delving into the Latest Updates on CVN-424 with Synapse”. Synapse. 5 February 2025. Retrieved 25 February 2025.
- 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.
- 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
////////////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
- 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.
- 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
- 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
- “BNC 210”. AdisInsight. 30 December 2024. Retrieved 22 February 2025.
- “Delving into the Latest Updates on BNC-210 with Synapse”. Synapse. 23 January 2025. Retrieved 22 February 2025.
- 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.
- “CID 24772165”. PubChem. Retrieved 5 January 2026.
- 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
Simedeutirom
Simedeutirom
CAS 2403721-24-2
MF C18H92H3Cl2N6O4 MW 450.25
2-[3,5-Dichloro-4-[[(7R)-2,5,6,7-tetrahydro-7-(methyl-d3)-1-oxo-1H-cyclopenta[d]pyridazin-4-yl]oxy]phenyl]-2,3,4,5-tetrahydro-3,5-dioxo-1,2,4-triazine-6-carbonitrile
2-[3,5-dichloro-4-[[(7R)-1-oxo-7-(trideuteriomethyl)-2,5,6,7-tetrahydrocyclopenta[d]pyridazin-4-yl]oxy]phenyl]-3,5-dioxo-1,2,4-triazine-6-carbonitrile
2-(3,5-dichloro-4-{[(7R)-7-(2H3)methyl-1-oxo-2,5,6,7-tetrahydro-1Hcyclopenta[d]pyridazin-4-yl]oxy}phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile
thyroid hormone beta receptor agonist, 4G7Z7KQ8GV
Simedeutirom is a selective, synthetic, deuterium-labeled thyroid hormone receptor beta (THR-β) agonist. It features a novel cyclopenta𝑑pyridazine core and is primarily utilized as a specialized tool compound in the biochemical research of metabolic diseases, including obesity, type 2 diabetes mellitus, and related metabolic disorders.
Core Structural & Pharmacological Profile
- Target Selectivity: It functions as a potent agonist specifically targeting the thyroid hormone receptor beta (THR-β), with an half-maximal effective concentration (EC₅₀) ranging between 0.1 to 1 μM. THR-β activation plays a foundational role in modulating hepatic lipid metabolism, lowering cholesterol, and regulating overall energy expenditure without heavily triggering the alpha receptor (THR-α), which is associated with adverse cardiac side effects.
- Deuterium Labeling: The compound incorporates deuterium (a stable isotope of hydrogen) into its chemical architecture, specifically modified as a trideuteriomethyl group. Isotopic modification or “deuteration” is an established medicinal chemistry approach frequently evaluated to slow metabolic clearance and increase structural stability.
- Chemical Identifiers:
- Molecular Formula: C₁₈H₁₂Cl₂N₆O₄
- Molecular Weight: 450.25 g/mol
- CAS Registry Number: 2403721-24-2
- FDA UNII Code: 4G7Z7KQ8GV
Research Context & Status
Simedeutirom is categorized under the International Nonproprietary Name (INN) database. However, it is fundamentally classified for in vitro and in vivo research use only. It has not been approved for clinical therapeutic use or direct distribution to patients.
PAT
WO 2019240938
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019240938&_cid=P11-MU978W-22170-1
PAT
US20250179050
Example 1 Preparation of crude free base of compound I
Step 1: preparation of compound b
N-(3,5-dichloro-4-((7-(methyl-d3)-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [d]pyridazin-4-yl)oxy)phenyl)benzamid
| 1H NMR (400 MHZ, DMSO) δ 12.07 (s, 1H), 10.55 (s, 1H), 8.04 (s, 2H), 7.98-7.95 (m, 2H), 7.63-7.50 (m, 3H), 3.29-3.25 (m, 1H), 3.02-2.90 (m, 2H), 2.39-2.36 (m, 1H), 1.75-1.72 (m, 1H). |
Step 2: preparation of compound c
4-(4-amino-2,6-dichlorophenoxy)-7-(methyl-d3)-2,5,6,7-tetrahydro-1H-cyclopenta [d]pyridazin-1-on
| To a 100 L reaction kettle, 5.76 kg of the crude compound b from the previous step, a potassium hydroxide solution (2606 g KOH dissolved in 19.5 L of purified water) and 6.0 L of anhydrous ethanol were added under stirring. After the complete addition, the mixture was heated to reflux and reacted for about 16 hours, and the raw material was controlled for a complete reaction. |
| 1H NMR (400 MHZ, DMSO) δ 11.98 (s, 1H), 6.67 (m, 2H), 5.60 (s, 2H), 3.30-3.19 (m, 1H), 3.03-2.93 (m, 1H), 2.90-2.70 (m, 1H), 2.35 (m, 1H), 1.69 (m, 1H). |
Step 3: preparation of compound d
(R)-4-(4-amino-2,6-dichlorophenoxy)-7-(methyl-d3)-2,5,6,7-tetrahydro-1H-cyclopenta [d]pyridazin-1-one
| 3298 g of racemate c was subjected to chiral resolution to give, two optical isomers from separation: |
| Compound d (retention time: 1.583 min, 1230 g, off-white solid, ee %=99.60%, yield 37.3%); and compound d-1 (retention time: 1.926 min, 1255 g, off-white solid, ee %=99.76%, yield 38.1%). |
Resolution conditions:
Compound d
| 1H NMR (400 MHZ, DMSO) δ 11.98 (s, 1H), 6.67 (s, 2H), 5.60 (s, 2H), 3.30-3.19 (m, 1H), 3.03-2.93 (m, 1H), 2.90-2.70 (m, 1H), 2.35 (dtd,1H), 1.69 (ddt, 1H). |
Compound d-1
| 1H NMR (400 MHZ, DMSO) δ 11.98 (s, 1H), 6.68 (d, 2H), 5.60 (s, 2H), 3.29-3.18 (m, 1H), 2.97 (tdd, 1H), 2.90-2.72 (m, 1H), 2.35 (dtd, 1H), 1.69 (ddt, 1H). |
Step 4: preparation of compound e
Ethyl(R,Z)-(2-cyano-2-(2-(3,5-dichloro-4-((7-(methyl-d3)-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [d]pyridazin-4-yl)oxy)phenyl) hydrazineylidene) acetyl) carbamate
| To a 100 L reaction kettle, 16.0 kg of acetic acid, 4.0 kg of purified water and 2.0 kg of compound d were added with stirring. The temperature was reduced to 0+5° C., then 2.36 kg of hydrochloric acid was added, and after the addition, the temperature was maintained at 0+5° C. with stirring for about 20 minutes. A sodium nitrite solution (0.5 kg of sodium nitrite dissolved in 1.0 kg of purified water) was dropwise added with the temperature being controlled at 0+5° C., and after the addition, the temperature was maintained at 0+5° C. for reaction for 2 hours. The temperature was controlled at 5+5° C. and a sodium acetate solution (1.5 kg of sodium acetate dissolved in 6.0 kg of purified water) was added dropwise, then 0.99 kg of N-cyanoacetourethane was added, and then the temperature was increased to 10+5° C. for a reaction for about 2 hours. Then a sample was taken for HPLC monitoring, after which time samples were taken at each about 2-hour interval, and the reaction was not stopped until the content of compound d was determined by HPLC to be≤1.0%. |
| The filter cake was dried at 55+5° C. with vacuum≤−0.07 MPa for about 17 hours, and compound e was obtained and collected, weighing 2.6327 kg. |
| 1H NMR (400 MHZ, DMSO) δ 12.08 (d, 2H), 10.88 (s, 1H), 7.99 (s, 2H), 4.21 (q, 2H), 3.30-3.17 (m, 1H), 3.08-2.95 (m, 1H), 2.95-2.80 (m, 1H), 2.38 (ddd, 1H), 1.78-1.63 (m, 1H), 1.28 (t, 3H). |
Step 5: preparation of compound of formula I
(R)-2-(3,5-dichloro-4-((7-(methyl-d3)-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [d]pyridazin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile
| 1H NMR (400 MHZ, DMSO) δ 13.26 (s, 1H), 12.09 (s, 1H), 7.79 (s, 2H), 3.32-3.24 (m, 1H), 3.10-2.99 (m, 1H), 2.96-2.88 (m, 1H), 2.45-2.31 (m, 1H), 1.77-1.69 (m, 1H). |
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References
- Method for preparing (r)-1,4-dichloro-5-(methyl-d3)-6,7-dihydro-5h-cyclopenta[d]pyridazinePublication Number:WO-2025055949-A1Priority Date:2023-09-12
- Polymorph as thyroid hormone receptor agonists and use thereofPublication Number:WO-2023147752-A1Priority Date:2022-02-07
- Preparation method of pyridazinone derivative, and intermediate thereofPublication Number:TW-202342457-APriority Date:2022-02-07
- Preparation method of pyridazinone derivative, and intermediate thereofPublication Number:WO-2023147779-A1Priority Date:2022-02-07
- Polymorph as thyroid hormone receptor agonists and use thereofPublication Number:EP-4477652-A1Priority Date:2022-02-07
////////simedeutirom, anax labs, thyroid hormone beta receptor agonist, 4G7Z7KQ8GV
#simedeutirom, #anax labs, #thyroid hormone beta receptor agonist, #4G7Z7KQ8GV
Silevertinib
Silevertinib
CAS 2607829-38-7
MF C30H30ClFN6O2 MW561.0 g/mol
(E)-N-[4-(3-chloro-2-fluoroanilino)-7-[2-[(1R,5S)-3-methyl-3-azabicyclo[3.1.0]hexan-1-yl]ethynyl]quinazolin-6-yl]-4-morpholin-4-ylbut-2-enamide
(2E)-N-[4-(3-chloro-2-fluoroanilino)-7-{[(1R,5S)-3-methyl-3-azabicyclo[3.1.0]hexan-1-yl]ethynyl}quinazolin-6-yl]-4-(morpholin-4-yl)but-2-enamide
epidermal growth factor receptor tyrosine kinase inhibitor, antineoplastic, BDTX-1535, BDTX 1535, CANCER, Glioblastoma, Black Diamond Therapeutics, RP9F537KVY
Silevertinib is an investigational new drug that is being evaluated by Black Diamond Therapeutics for the treatment of glioblastoma and non-small cell lung cancer.[1] It is a EGFR protein tyrosine kinase inhibitor.[1][2]
Silevertinib (formerly known as BDTX-1535) is an investigational, orally bioavailable, fourth-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) developed by Black Diamond Therapeutics. It is specifically engineered to be brain-penetrant and to target a broad spectrum of both classical and non-classical EGFR mutations, as well as resistance mutations, while sparing wild-type EGFR to reduce side effects.
Silevertinib is an orally bioavailable, brain penetrating, mutant-selective, epidermal growth factor receptor (EGFR) inhibitor, with potential antineoplastic activity. Upon oral administration, silevertinib selectively targets, irreversibly binds to, and inhibits the activity of various EGFR alterations and mutations, including certain intrinsic and acquired resistance mutations. This prevents EGFR-mediated signaling in susceptible tumor cells. This may both induce cell death and inhibit tumor growth in EGFR-overexpressing tumor cells. EGFR, a receptor tyrosine kinase mutated in many tumor cell types, plays a key role in tumor cell proliferation and tumor vascularization.
Mechanism of Action
Silevertinib works by selectively and irreversibly binding to mutated EGFR receptors. EGFR is a receptor tyrosine kinase that, when mutated, triggers uncontrolled cell division and tumor vascularization. By shutting down this signaling cascade, silevertinib induces tumor cell death and inhibits further growth.
A major clinical advantage of the drug is its ability to cross the blood-brain barrier, allowing it to target central nervous system (CNS) tumors and brain metastases that many traditional therapies fail to reach.
Target Indications & Clinical Data
Silevertinib is primarily being studied for two aggressive types of cancer:
- Non-Small Cell Lung Cancer (NSCLC): It targets frontline patients with classical and over 50 non-classical EGFR driver mutations, as well as patients who have developed the acquired C797S resistance mutation from prior treatments. Phase 2 clinical trial data presented at the American Society of Clinical Oncology (ASCO) 2026 Annual Meeting showcased robust efficacy:
- Objective Response Rate (ORR): 60% in treatment-naïve patients.
- CNS Response Rate: An impressive 86% intracranial ORR in patients presenting with brain metastases.
- Disease Control Rate (DCR): 91%.
- Glioblastoma Multiforme (GBM): In May 2026, a randomized Phase 2 trial was initiated for newly diagnosed patients with EGFRvIII-positive, MGMT-negative glioblastoma, evaluating silevertinib in combination with temozolomide.
Safety Profile & Side Effects
The adverse events of silevertinib are consistent with the broader class of EGFR inhibitors. The most frequently reported treatment-related adverse events (TRAEs) include:
- Rash
- Diarrhea
- Stomatitis (mouth sores)
- Paronychia (nail bed inflammation)
While a high percentage of patients (up to 77–84%) require dose reductions to manage these side effects, data shows that 86% of responding patients maintained or deepened their clinical response even after dropping to a lower dose. The treatment discontinuation rate remains low at roughly 9–14%, indicating the drug is manageable for long-term therapy.
Regulatory Status
As an investigational drug, silevertinib is not yet approved for commercial use by global regulatory agencies. However, the manufacturer anticipates regulatory feedback from the US FDA regarding its registration pathway for first-line NSCLC therapy.
- OriginatorBlack Diamond Therapeutics
- Class2 ring heterocyclic compounds; Amides; Amines; Aniline compounds; Antineoplastics; Halogenated hydrocarbons; Morpholines; Quinazolines; Small molecules
- Mechanism of ActionErbB receptor antagonists
- Phase IIGlioblastoma
- Phase I/IINon-small cell lung cancer
- Phase 0Glioma
- 06 Aug 2026Black Diamond Therapeutics anticipates regulatory feedback from the US FDA on registration path of silevertinib for Non-small cell lung cancer (First-line therapy) in the fourth quarter of 2026 (Black Diamond pipeline, May 2026)
- 02 Jun 2026Efficcay and adverse event data from phase I/II trial in Non-small cell lung cancer presented at the 62nd Annual Meeting of the American Society of Clinical Oncology (ASCO-2026)
- 21 May 2026Efficacy and adverse events data from a phase I/II trial in Non small cell lung cancer released by Black Diamond Therapeutics
SYN
- BDTX-1535 Goes after Osimertinib ResistancePublication Name:Cancer DiscoveryPublication Date:2021-12-01PMID:34702733DOI:10.1158/2159-8290.cd-nb2021-0395
- Further characterization of a DNA polymerase activity in mouse sperm nucleiPublication Name:Biochimica et Biophysica Acta (BBA) – Nucleic Acids and Protein SynthesisPublication Date:1976-10-04PMID:10003DOI:10.1016/0005-2787(76)90342-7
PAT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021030711&_cid=P21-MU6CBO-49598-1
Example 33. Synthesis of Compound No. 37 ((E)-N-(4-((3-chloro-2-fluorophenyl)amino)-7-(((1R,5S)-3-methyl-3-azabicyclo[3.1.0]hexan-1-yl)ethynyl)quinazolin-6-yl)-4-morpholinobut-2-enamide)
PAT
WO2026064728
PAT
US20220298120
https://patentscope.wipo.int/search/en/detail.jsf?docId=US375116378&_cid=P21-MU6C60-41372-1
Example 33. Synthesis of Compound No. 37 ((E)-N-(4-((3-chloro-2-fluorophenyl)amino)-7-(((1R,5S)-3-methyl-3-azabicyclo[3.1.0]hexan-1-yl)ethynyl)quinazolin-6-yl)-4-morpholinobut-2-enamide)
| Step 1. To a solution of (E)-4-bromobut-2-enoic acid (5.00 g, 30.3 mmol) and dimethylformamide (22.2 mg, 303 umol) in dichloromethane (20 mL) was added (COCl) 2 (3.85 g, 30.3 mmol) dropwise at 0° C. under N 2. The mixture was stirred at 0-25° C. for 4 h. On completion, the reaction mixture was concentrated in vacuo to give (E)-4-bromobut-2-enoyl chloride (5.8 g, crude) as a yellow oil. |
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References
- “Silevertinib”. AdisInsight. Springer Nature Switzerland AG. Retrieved 5 July 2026.
- Joshi H, Sheikh MS (August 2025). “Cell Death, Molecular Targeted Therapies, and Metabolic Reprogramming in EGFR-Mutant Lung Cancer”. Cancers. 17 (17). Basel: 2791. doi:10.3390/cancers17172791. PMC 12427363. PMID 40940888.
PAT
- Polymorphs as erbb inhibitorsPublication Number:EP-4405350-A1Priority Date:2021-09-21
- Polymorphs as erbb inhibitorsPublication Number:US-2024425492-A1Priority Date:2021-09-21
- Polymorphs as erbb inhibitorsPublication Number:WO-2023049168-A1Priority Date:2021-09-21
- Method of treating cancers with alkyne substituted quinazoline derivativesPublication Number:WO-2022094464-A1Priority Date:2020-11-02
- Alkynyl quinazoline compoundsPublication Number:EP-4013749-A1Priority Date:2019-08-15
- Alkynyl quinazoline compoundsPublication Number:US-2022298120-A1Priority Date:2019-08-15
- Alkynyl quinazoline compoundsPublication Number:US-2026049063-A1Priority Date:2019-08-15
- Alkynyl quinazoline compoundsPublication Number:US-12435046-B2Priority Date:2019-08-15Grant Date:2025-10-07
- Alkynyl quinazoline compoundsPublication Number:EP-4013749-B1Priority Date:2019-08-15Grant Date:2026-03-11
- Alkynyl quinazoline compoundsPublication Number:WO-2021030711-A1Priority Date:2019-08-15
 | |
| Clinical data | |
|---|---|
| Other names | RVU-120 |
| Identifiers | |
| IUPAC name | |
| CAS Number | 2607829-38-7 |
| PubChem CID | 156071569 |
| IUPHAR/BPS | 13371 |
| UNII | RP9F537KVY |
| KEGG | D13300 |
| Chemical and physical data | |
| Formula | C30H30ClFN6O2 |
| Molar mass | 561.06 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| SMILES | |
| InChI | |
///////////silevertinib, anax labs, epidermal growth factor receptor tyrosine kinase inhibitor, antineoplastic, BDTX-1535, BDTX 1535, CANCER, Glioblastoma, Black Diamond Therapeutics, RP9F537KVY
#silevertinib, #anax labs, #epidermal growth factor receptor tyrosine kinase inhibitor, #antineoplastic, #BDTX-1535, #BDTX 1535, #CANCER, #Glioblastoma, #Black Diamond Therapeutics, #RP9F537KVY
Floretyrosine F 18
Floretyrosine F 18
CAS 178433-03-9
FormulaC₁₁H₁₄[¹⁸F]NO₃
Molecular Weight226.23 g/mol
FDA UNII1326R5J1IA
FDA 2026, APPROVALS 2026, Pixclara, TELIX PHARMACEUTICALS, GLIOMA, CANCER, TLX101-CDx, TLX101-Px, 1326R5J1IA, L-(18F)FET, O-(2-((18)F)fluoroethyl)-L-tyrosine
(2S)-2-amino-3-[4-(2-[¹⁸F]fluoroethoxy)phenyl]propanoic acid, (2S)-2-amino-3-[4-(2-(18F)fluoroethoxy)phenyl]propanoic acid
To use with positron emission tomography to differentiate recurrent or progressive glioma from treatment-related change in conjunction with other diagnostic evaluations
Floretyrosine F 18 (brand name Pixclara®, also known as 18F-FET) is a newly FDA-approved radiopharmaceutical imaging drug used in positron emission tomography (PET) scans for patients with glioma (brain cancer). Developed by Telix Pharmaceuticals, it received formal U.S. Food and Drug Administration (FDA) approval on September 14, 2026, making it the first and only approved FET-PET diagnostic tracer for brain tumors in the United States.
Primary Clinical Indication
Pixclara is indicated for use in both adult and pediatric patients (1 month of age and older).
Its primary clinical purpose is to differentiate recurrent or progressive glioma from treatment-related changes (such as radiation necrosis or inflammation). Following chemotherapy or radiation, traditional MRI scans often show areas that “light up,” making it incredibly difficult for neuro-oncologists to tell whether a tumor is growing back or if the brain is simply healing from harsh treatments. Pixclara solves this diagnostic dilemma by providing metabolic clarity.
How It Works (Mechanism of Action)
- Targeted Delivery: Floretyrosine F 18 is a synthetic amino acid analogue labeled with the radioactive isotope fluorine-18. [1, 2]
- Cellular Uptake: Once injected intravenously, it specifically targets and binds to L-type amino acid transporters 1 and 2 (LAT1 and LAT2). These transporters are heavily overexpressed on the membranes of active glioma cells compared to healthy brain tissue.
- PET Detection: The tumor cells rapidly absorb the tracer, and the energy emissions from the fluorine-18 isotope are captured by a PET scanner, creating a highly accurate metabolic map of the tumor.
Strategic & Future Impact
The approval aligns U.S. practice with international clinical guidelines—such as the National Comprehensive Cancer Network (NCCN) Guidelines®—which already recommend FET-PET imaging for brain tumor management. Furthermore, Telix Pharmaceuticals is currently conducting a Phase 3 registrational study to expand Pixclara’s indication to include the diagnosis and characterization of brain metastases (cancers that have spread to the brain from other parts of the body)
Fluoroethyl-l-tyrosine (18F), commonly known as [18F]FET, is a radiopharmaceutical tracer used in positron emission tomography (PET) imaging. This synthetic amino acid, labeled with the radioactive isotope fluorine-18, is a valuable radiopharmaceutical tracer for use in neuro-oncology for diagnosing, planning treatment, and following up on brain tumors such as gliomas. The tracer’s ability to provide detailed metabolic imaging of tumors makes it an essential tool in the clinical management of brain cancer patients. Continued advancements in PET imaging technology and the development of more efficient synthesis methods are expected to further enhance the clinical utility of [18F]FET.[2]
Radiosynthesis
There are two common pathways for the radiosynthesis of [18F]FET. The first one utilizes a nucleophilic 18F-fluorination of ethyleneglycol-1,2-ditosylate with a subsequent 18F-fluoroethylation of a precursor di-sodium salt of L-tyrosine. This sequence requires two purification steps, two different precursors and a dual-reactor synthesis module which is not widely available in research or commercial centers.[3][4][5] The schematic for this pathway is:[6]
The second route of radiosynthesis is a direct nucleophilic 18F-fluorination a TET (O-(2-tosyloxy-ethyl)-N-trityl-L-tyrosine tert-butyl ester) protected precursor followed by acidic hydrolysis of protecting groups.[3][4][7] The schematic for this pathway is:[6]
REF
- Fluorinated phenylalanines: synthesis and pharmaceutical applicationsPublication Name:Beilstein Journal of Organic ChemistryPublication Date:2020-05-15PMCID:PMC7237815PMID:32509033DOI:10.3762/bjoc.16.91
- Solid-Phase Synthesis of O-(2-[18F]-Fluoro-ethyl)-l-tyrosinePublication Name:SynfactsPublication Date:2013-03-15DOI:10.1055/s-0032-1318420
- Investigations into the synthesis, radiofluorination and conjugation of a new [18F]fluorocyclobutyl prosthetic group and its in vitro stability using a tyrosine model systemPublication Name:Bioorganic & Medicinal ChemistryPublication Date:2013-02-01PMID:23290251DOI:10.1016/j.bmc.2012.11.049
- Microfluidic technology: An economical and versatile approach for the synthesis of O-(2-[18F]fluoroethyl)-l-tyrosine ([18F]FET)Publication Name:Bioorganic & Medicinal Chemistry LettersPublication Date:2012-03-15PMID:22342141DOI:10.1016/j.bmcl.2012.01.083
- Synthesis and biological evaluation of novel F-18 labeled pyrazolo[1,5-a]pyrimidine derivatives: Potential PET imaging agents for tumor detectionPublication Name:Bioorganic & Medicinal Chemistry LettersPublication Date:2011-08-15PMID:21752641DOI:10.1016/j.bmcl.2011.06.072
- (18)F Labeled benzimidazole derivatives as potential radiotracer for positron emission tomography (PET) tumor imagingPublication Name:Bioorganic & Medicinal ChemistryPublication Date:2010-04-01PMID:20303769DOI:10.1016/j.bmc.2010.02.060
- No carrier added synthesis of O-(2′-[18F]fluoroethyl)-l-tyrosine via a novel type of chiral enantiomerically pure precursor, NiII complex of a (S)-tyrosine Schiff basePublication Name:Bioorganic & Medicinal ChemistryPublication Date:2008-05-01PMID:18378460DOI:10.1016/j.bmc.2008.03.040
- Solid-Phase Synthesis of O-(2-[18F]-Fluoro-ethyl)-l-tyrosine, DOI:10.1055/s-0032-1318420, Publication Date:2013, Publication Name:Synfacts
SYN
US20190223814/US249082034
PAT
US20120189546
https://patentscope.wipo.int/search/en/detail.jsf?docId=US73636763&_cid=P11-MU3HO5-37901-1
PAT
US20140235861
https://patentscope.wipo.int/search/en/detail.jsf?docId=US107206441&_cid=P11-MU3HO5-37901-1
Another example of an 18F-fluoroalkylation reaction to obtain a PET tracer is the reaction described by Wang et al (2006 J Radioanalyt Nuc Chem; 270(2): 439-43) used to obtain the 18F-labeled amino acid O-(2-[ 18F]fluoroethyl)-L-tyrosine ([ 18F]FET):
[ 18F]Fluoroethyl tosylate was prepared in step (i) by displacement of a tosyl group from 1,2-bistosyloxyethane by reaction with K 18F/Kryptofix 2.2.2 in acetonitrile at 90° C. for 10 minutes. The purified [ 18F]fluoroethyl tosylate was then reacted in step (ii) with a solution of L-tyrosine and 10% aqueous NaOH in DMSO (or di-Na-salt of L-tyrosine in DMSO) 20 minutes at 90° C. to obtain [ 18F]FET. In contrast to the method for preparation of 18F-labelled S-fluoroalkyl diarylguanidines as reported by Robins et al (supra), this method for preparation of [ 18F]FET uses a soluble base in the alkylation reaction. However, the reaction is still not ideal for carrying out on an automated synthesis device that uses a cassette due to the fact that and additional vial is required for the base used for the subsequent fluoroalkylation step.
PAT
Radiation radiation detector with position tracking system and its use in medical systems and proceduresPublication Number:
JP-2004512502-APriority Date:2000-08-21
- Novel imaging agents and precursors and methods of preparation thereofPublication Number:CN-1234680-CPriority Date:2001-06-04Grant Date:2006-01-04
- Radioactive emission detector equipped with a position tracking system and utilization thereof with medical systems and in medical proceduresPublication Number:US-2005055174-A1Priority Date:2000-08-21
- Radioactive emission detector equipped with a position tracking system and utilization thereof with medical systems and in medical proceduresPublication Number:US-7826889-B2Priority Date:2000-08-21Grant Date:2010-11-02
- Radioactive emission detector equipped with a position tracking system and utilization thereof with medical systems and in medical proceduresPublication Number:US-2004015075-A1Priority Date:2000-08-21
- Radioactive emission detector equipped with a position tracking systemPublication Number:US-2014249402-A1Priority Date:2000-08-21
- Tumor imaging compoundsPublication Number:CA-2479514-CPriority Date:2002-04-30Grant Date:2011-07-26
- Protected tyrosine derivatives, method for the production thereof and use of the same for producing o-(2-[18f]-fluoroethyl)-l-tyrosinePublication Number:WO-02102765-A3Priority Date:2001-06-05
- Protected tyrosine derivatives, method for the production thereof and use of the same for producing o-(2-[18f]-fluoroethyl)-l-tyrosinePublication Number:US-2004192954-A1Priority Date:2001-06-05
- PROTECTED TYROSINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE FOR THE PRODUCTION OF O-(2-?18 F)-FLUORETHYL)-L-TYROSINEPublication Number:AT-E289992-T1Priority Date:2001-06-05Grant Date:2005-03-15
- Imaging agents, precursors thereof and methods of manufacturePublication Number:US-2003124059-A1Priority Date:2001-06-04
- Radioactively labelled amino acid analogues, their preparation and usePublication Number:US-2006127306-A1Priority Date:2002-08-02
- Radioactively labelled amino acid analogues, their preparation and usePublication Number:EP-1539250-A1Priority Date:2002-08-02
- Tumor imaging compoundsPublication Number:US-7989649-B2Priority Date:2002-04-30Grant Date:2011-08-02
- Tumor imaging compoundsPublication Number:US-2009240041-A1Priority Date:2002-04-30
- Tumor imaging compoundsPublication Number:US-7544715-B2Priority Date:2002-04-30Grant Date:2009-06-09
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References
- CID 54255856 from PubChem
- Treglia G, Muoio B, Giovanella L (2020). “18F-FET”. In Calabria F, Schillaci O (eds.). Radiopharmaceuticals: A Guide to PET/CT and PET/MRI. Cham: Springer International Publishing. pp. 83–88. doi:10.1007/978-3-030-27779-6_4. ISBN 978-3-030-27778-9.
- Bourdier T, Greguric I, Roselt P, Jackson T, Faragalla J, Katsifis A (July 2011). “Fully automated one-pot radiosynthesis of O-(2-[18F]fluoroethyl)-L-tyrosine on the TracerLab FX(FN) module”. Nuclear Medicine and Biology. 38 (5): 645–651. doi:10.1016/j.nucmedbio.2011.01.001. PMID 21718939.
- Siddiq IS, Atwa ST, Shama SA, Eltaoudy MH, Omar WM (March 2018). “Radiosynthesis and modified quality control of O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) for brain tumor imaging”. Applied Radiation and Isotopes. 133: 38–44. Bibcode:2018AppRI.133…38S. doi:10.1016/j.apradiso.2017.12.011. PMID 29275040.
- Wester HJ, Herz M, Weber W, Heiss P, Senekowitsch-Schmidtke R, Schwaiger M, et al. (January 1999). “Synthesis and radiopharmacology of O-(2-[18F]fluoroethyl)-L-tyrosine for tumor imaging”. Journal of Nuclear Medicine. 40 (1): 205–212. PMID 9935078.
- Wang M, Glick-Wilson BE, Zheng QH (December 2019). “Facile fully automated radiosynthesis and quality control of O-(2-[18F]fluoroethyl)-l-tyrosine ([18F]FET) for human brain tumor imaging”. Applied Radiation and Isotopes. 154 108852. Bibcode:2019AppRI.15408852W. doi:10.1016/j.apradiso.2019.108852. PMID 31442794.
- Mueller D, Klette I, Kalb F, Baum RP (July 2011). “Synthesis of O-(2-[18F]fluoroethyl)-L-tyrosine based on a cartridge purification method”. Nuclear Medicine and Biology. 38 (5): 653–658. doi:10.1016/j.nucmedbio.2011.01.006. PMID 21718940.
- Muoio B, Giovanella L, Treglia G (2018-09-04). “Recent Developments of 18F-FET PET in Neuro-oncology”. Current Medicinal Chemistry. 25 (26): 3061–3073. doi:10.2174/0929867325666171123202644. PMID 29173147.
- Wang L, Lieberman BP, Ploessl K, Kung HF (January 2014). “Synthesis and evaluation of ¹⁸F labeled FET prodrugs for tumor imaging”. Nuclear Medicine and Biology. 41 (1): 58–67. doi:10.1016/j.nucmedbio.2013.09.011. PMC 3895945. PMID 24183614.
- Lee TS, Ahn SH, Moon BS, Chun KS, Kang JH, Cheon GJ, et al. (August 2009). “Comparison of 18F-FDG, 18F-FET and 18F-FLT for differentiation between tumor and inflammation in rats”. Nuclear Medicine and Biology. 36 (6): 681–686. doi:10.1016/j.nucmedbio.2009.03.009. PMID 19647174.
- Leung K (2004), “O-(2-[18F]Fluoroethyl)-L-tyrosine”, Molecular Imaging and Contrast Agent Database (MICAD), Bethesda (MD): National Center for Biotechnology Information (US), PMID 20641653, retrieved 2024-07-10
- Heiss P, Mayer S, Herz M, Wester HJ, Schwaiger M, Senekowitsch-Schmidtke R (August 1999). “Investigation of transport mechanism and uptake kinetics of O-(2-[18F]fluoroethyl)-L-tyrosine in vitro and in vivo”. Journal of Nuclear Medicine. 40 (8): 1367–1373. PMID 10450690.
- Wang HE, Wu SY, Chang CW, Liu RS, Hwang LC, Lee TW, et al. (May 2005). “Evaluation of F-18-labeled amino acid derivatives and [18F]FDG as PET probes in a brain tumor-bearing animal model”. Nuclear Medicine and Biology. 32 (4): 367–375. doi:10.1016/j.nucmedbio.2005.01.005. PMID 15878506.
- Rau FC, Weber WA, Wester HJ, Herz M, Becker I, Krüger A, et al. (August 2002). “O-(2-[(18)F]Fluoroethyl)- L-tyrosine (FET): a tracer for differentiation of tumour from inflammation in murine lymph nodes”. European Journal of Nuclear Medicine and Molecular Imaging. 29 (8): 1039–1046. doi:10.1007/s00259-002-0821-6. PMID 12173018.
- Holzgreve A, Brendel M, Gu S, Carlsen J, Mille E, Böning G, et al. (2016-06-14). “Monitoring of Tumor Growth with [(18)F]-FET PET in a Mouse Model of Glioblastoma: SUV Measurements and Volumetric Approaches”. Frontiers in Neuroscience. 10: 260. doi:10.3389/fnins.2016.00260. PMC 4906232. PMID 27378835.
- “Product Characteristic of IASOglio©” (PDF). synektik.com.pl. 28 June 2024. Retrieved 28 June 2024.
- Pauleit D, Floeth F, Herzog H, Hamacher K, Tellmann L, Müller HW, et al. (April 2003). “Whole-body distribution and dosimetry of O-(2-[18F]fluoroethyl)-L-tyrosine”. European Journal of Nuclear Medicine and Molecular Imaging. 30 (4): 519–524. doi:10.1007/s00259-003-1118-0. PMID 12589478.
- Tang G, Tang X, Wang M, Luo L, Gan M (January 2004). “Radiation dosimetry of O-(3-[18F]fluoropropyl)-L-tyrosine as oncologic PET tracer based on the mice distribution data”. Applied Radiation and Isotopes. 60 (1): 27–32. doi:10.1016/j.apradiso.2003.10.005. PMID 14687633.
- Mattsson S, Johansson L, Leide Svegborn S, Liniecki J, Noßke D, Riklund KÅ, et al. (July 2015). “Radiation Dose to Patients from Radiopharmaceuticals: a Compendium of Current Information Related to Frequently Used Substances” (PDF). Annals of the ICRP. 44 (2 Suppl): 7–321. doi:10.1177/0146645314558019. PMID 26069086.
- “IASOglio”. Curium Pharma. Retrieved 2024-07-10.
 | |
| Clinical data | |
|---|---|
| Other names | 18F-FET; O-(2-(18F)fluoroethyl)-l-tyrosine, O-(2-Fluorethyl)-l-thyrosine, l-(18F)FET[1] |
| Routes of administration | Intravenous |
| ATC code | V09IX10 (WHO) |
| Identifiers | |
| IUPAC name | |
| CAS Number | 178433-03-9 |
| PubChem CID | 9834479 |
| ChemSpider | 8010200 |
| UNII | 1326R5J1IA |
| CompTox Dashboard (EPA) | DTXSID601045942  |
| Chemical and physical data | |
| Formula | C11H14FNO3 |
| Molar mass | 227.235 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| SMILES | |
| InChI | |
///////////floretyrosine F 18, anax labs, FDA 2026, APPROVALS 2026, Pixclara, TELIX PHARMACEUTICALS, GLIOMA, CANCER, TLX101-CDx, TLX101-Px, 1326R5J1IA, L-(18F)FET, O-(2-((18)F)fluoroethyl)-L-tyrosine
#floretyrosine F 18, #anax labs, #FDA 2026, #APPROVALS 2026, #Pixclara, #TELIX PHARMACEUTICALS, #GLIOMA, #CANCER, #TLX101-CDx, #TLX101-Px, #1326R5J1IA, #L-(18F)FET, #O-(2-((18)F)fluoroethyl)-L-tyrosine
Setomagpran
Setomagpran
CAS 2991434-57-0
MF C22H19Cl2F6N5O MW 554.316
3-chloro-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide
1H-Pyrazole-4-carboxamide, 3-chloro-N-[(1R,3S)-3-[[6-chloro-2-(trifluoromethyl)-4-quinolinyl]amino]cyclohexyl]-1-(2,2,2-trifluoroethyl)-
3-chloro-N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)quinolin-4-yl]amino}cyclohexyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide
Mas-related G protein-coupled receptor antagonist, anti-inflammatory, MYX4KT647F
Setomagpran is a synthetic, small-molecule antagonist of the Mas-related G protein-coupled receptor X2 (MRGPRX2).
Because it blocks this specific receptor, it exhibits notable anti-inflammatory activity. The compound is primarily utilized as a reference standard and biochemical reagent in laboratory research settings
Setomagpran is the antagonist for mas-related G protein-coupled receptor (MRGPR), and exhibits anti-inflammatory activity.
Pat
Example 30
Synthesis of Example 30
Synthesis of 3-chloro-N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino) cyclohexyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide
Pat
WO 2022/067094 A1 (US20220098155)
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2022067094&_cid=P10-MTZI7E-88068-1
PAT
WO 2023/192901 A1
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023192901&_cid=P10-MTZIR9-08517-1
EXAMPLE 30
Synthesis of 3-chloro-N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino) cyclohexyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide
To a stirring solution of ethyl 3-chloro-1H-pyrazole-4-carboxylate (200 mg, 1 Eq, 1.15 mmol) in DMF (5 mL) at room temperature was added cesium carbonate (1.12 g, 3 Eq, 3.44 mmol) portionwise over 2 minutes. After stirring for 30 minutes, 2,2,2- Trifluoroethyl trifluoromethanesulfonate (798 mg, 3 Eq, 3.44 mmol) was added dropwise over 2 minutes. The reaction mixture was stirred for 14 h. Water (5 mL) was added and the mixture wasextracted with EtOAc (3 x 5 mL), dried over sodium sulfate, filtered through Celite, and concentrated in vacuo to afford an 87:13 mixture of ethyl 3-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylate and ethyl 5-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylate that was used without further purification.
To a stirring solution of the crude ethyl 3-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylate and 5-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylate mixture (294 mg, 1 Eq, 1.15 mmol) in THF (6 mL) was added an aqueous solution of 1M sodium hydroxide (5.7 mL, 5 Eq, 5.73 mmol). The reaction mixture was heated at 50 °C for 14 h. 10 mL of 3 M HCl was added. The aqueous layer was extracted with EtOAc (3 x 10 mL), dried over sodium sulfate, filtered through Celite, and concentrated in vacuo to afford a mixture of 3-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylic acid and 5-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylic acid (276 mg, 1.21 mmol, 105 %) that was used without further purification.
To a stirring solution of (1S,3R)-N1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine hydrochloride (100 mg, 1 Eq, 0.264 mmol) in DMF (1.5 mL) were added a crude mixture of 3-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylic acid and 5-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylic acid (60 mg, 1 Eq, 0.264 mmol), N-ethyl-N-isopropylpropan-2-amine (DIPEA) (0.138 mL, 3 Eq, 0.793 mmol) and HATU (111 mg, 1.1 Eq, 0.291 mmol). The reaction mixture was stirred at room temperature for 2 h. Purification by reversed phase HPLC (35 55% 0.1% formic acid in MeCN and 0.1% formic acid in H2O) afforded 3-chloro-N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide (69 mg, 47% yield).
LCMS-ESI (m/z) calculated: 553.09 found 553.8 [M+H]+, RT = 10.114 min (Method 1)
1H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 10.9 Hz, 1H), 8.35 (s, 1H), 8.06 (d, J = 7.9 Hz, 1H), 7.90 (d, J = 9.0 Hz, 1H), 7.74 (dd, J = 9.0, 2.3 Hz, 1H), 7.48 (d, J = 7.9 Hz, 1H), 5.21 (q, J = 9.0 Hz, 1H), 4.01-3.83 (m, 2H), 2.17 (d, J = 12.0 Hz, 1H), 2.00-1.78 (m, 3H), 1.61-1.21 (m, 4H).
PAT
WO 2021/092240 A1
PAT
WO 2025/222040 A1
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References
- Modulators of mas-related g-protein receptor x2 and related products and methodsPublication Number:US-2024124416-A1Priority Date:2022-03-30
- Modulators of mas-related g-protein receptor x2 and related products and methodsPublication Number:US-2024059667-A1Priority Date:2022-03-30
- Modulators of mas-related g-protein receptor x2 and related products and methodsPublication Number:US-2024124414-A1Priority Date:2022-03-30
- Quinoline derivatives as modulators of mas-related g-protein receptor x2 and related productsPublication Number:WO-2023192901-A1Priority Date:2022-03-30
- Modulators of mas-related g-protein receptor x2 and related products and methodsPublication Number:US-2024124415-A1Priority Date:2022-03-30
- Modulators of Mas-related G-protein receptor X2 and related products and methodsPublication Number:US-12129243-B2Priority Date:2022-03-30Grant Date:2024-10-29
- Quinoline derivatives as modulators of mas-related g-protein receptor x2 and related productsPublication Number:WO-2023192901-A9Priority Date:2022-03-30
- Modulators of Mas-related G-protein receptor X2 and related products and methodsPublication Number:US-12129244-B2Priority Date:2022-03-30Grant Date:2024-10-29
- Modulators of mas-related g-protein receptor x2 and related products and methodsPublication Number:US-2025026735-A1Priority Date:2022-03-30
- Quinoline derivatives as modulators of mas-related g-protein receptor x2 and related productsPublication Number:EP-4499632-A1Priority Date:2022-03-30
//////////setomagpran, anax labs, Mas-related G protein-coupled receptor antagonist, anti-inflammatory, MYX4KT647F
#setomagpran, #anax labs, #Mas-related G protein-coupled receptor antagonist, #anti-inflammatory, #MYX4KT647F
Seldegamadlin
Seldegamadlin
CAS 2713618-08-5
MFC48H52Cl2FN7O6 MW912.9 g/mol
- (3’R,4’S,5’R)-6”-chloro-4′-(3-chloro-2-fluorophenyl)-N-((1r,4R)-4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-1-carbonyl)cyclohexyl)-2”-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3”-indoline]-5′-carboxamide
- (3’R,4’S,5’R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-N-((1r,4R)-4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-1-carbonyl)cyclohexyl)-2”-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamide
(3’R,4’S,5’R)-6”-chloro-4′-(3-chloro-2-fluorophenyl)-N-[trans-4-(4-{1-[(3RS)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzimidazol-5-yl}piperidine-1-carbonyl)cyclohexyl]-2”-oxo-1”,2”-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3”-indole]-5′-carboxamide
E3 ubiquitin-protein ligase Mdm2 (Hdm2) degrader, antineoplastic, KT 253, KT-253, VNP2BV6KGL
Seldegamadlin (also known as KT-253) is an advanced experimental oncology drug designed as a first-in-class, highly potent MDM2 PROTAC degrader and p53 stabilizer. It utilizes targeted protein degradation (TPD) technology to selectively eliminate the MDM2 oncoprotein, which restores the normal function of the critical tumor suppressor protein, p53.
How it Works
- Targeted Protein Degradation: It acts as a heterobifunctional PROTAC (proteolysis-targeting chimera). It features one end that binds tightly to MDM2 and another end that recruits the cereblon (CRBN) E3 ubiquitin ligase.
- p53 Stabilization: By tethering them together, it forces the cell’s natural disposal machinery to ubiquitinate and rapidly destroy MDM2. Because MDM2 normally suppresses and destroys p53, deleting MDM2 leads to an immediate up-regulation and stabilization of active p53.
- Apoptosis Activation: The sudden resurgence of active p53 fires up downstream targets like p21, forcing wild-type p53 cancer cells to halt their cell cycle (at the G2/M phase) and trigger rapid programmed cell death (apoptosis).
Primary Areas of Research
Seldegamadlin is actively being evaluated and researched for therapeutic efficacy against specific wild-type p53 malignancies:
- Hematologic Tumours: Including Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL).
- Solid Tumours: Such as Diffuse Large B-cell Lymphoma (DLBCL) and other forms retaining functional p53 signaling pathways
PAT
WO2023049790
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023049790&_cid=P11-MTWC17-46822-1
[001997] 3-[5-[1-(4-aminocyclohexanecarbonyl)-4-piperidyl]-3-methyl-2-oxo-benzimidazol-1-
yl]piperidine-2,6-dione (Intermediate WP)
[001998] Step 1 – Tert-butyl N-[4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-1-carbonyl]cyclohexyl]carbamate. A mixture of 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione (200 mg, 584 umol, Intermediate HE), (1s,4s)-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid (142 mg, 584 umol, CAS# 53292-90-3), 1-methylimidazole (1.53 g, 18.6 mmol) , and TCFH (409 mg, 1.46 mmol) in ACN (1 mL) was stirred at 25 °C for 1 min. On completion, the reaction mixture was concentrated to give a residue. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to give the title compound (120 mg, 36% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.11 (s, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 5.34 (dd, J = 5.6, 12.8 Hz, 1H), 4.62 – 4.54 (m, 1H), 4.10 – 3.98 (m, 1H), 3.49 ( s, 1H), 3.33 – 3.31 (m, 4H), 3.18 – 3.05 (m, 1H), 2.96 – 2.85 (m, 1H), 2.83 – 2.74 (m, 1H), 2.71 -2.62 (m, 3H), 2.05 – 1.94 (m, 1H), 1.86 – 1.67 (m, 6H), 1.61 – 1.40 (m, 7H), 1.39 (s, 9H).
[001999] Step 2 – 3-[5-[1-(4-aminocyclohexanecarbonyl)-4-piperidyl]-3-methyl-2-oxo-benzimidazol -1-yl]piperidine-2,6-dione. To a solution of tert-butyl N-[4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl] piperidine-1-carbonyl]cyclohexyl]carbamate (60.0 mg, 105 umol) in DCM (1 mL) was added TFA (1.54 g, 13.5 mmol). The mixture was then stirred at 25 °C for 2 mins. On completion, the mixture was concentrated in vacuo to give the title compound (50.0 mg, 80% yield, TFA) as brown oil. LC-MS (ESI+) m/z 468.1 (M+H)+.
[00812] (3’R,4’S,5’R)-6”-chloro-4′-(3-chloro-2-fluorophenyl)-2”-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3”-indoline]-5′-carboxylic acid (Intermediate CI)
[00813] Step 1 – (3E)-6-chloro-3-[(3-chloro-2-fluoro-phenyl)methylene]indolin-2-one. A 500 mL 3-necked round bottom flask was charged with 6-chloroindolin-2-one (89.6 g, 535 mmol, CAS# 56341-37-8), 3-chloro-2-fluoro-benzaldehyde (84.8 g, 535 mmol, CAS# 85070-48-0), MeOH (1700 mL) and piperidine (9.11 g, 107 mmol). The mixture was stirred at 65 °C for 5 h, then at 25 °C for 12 h. On completion, the reaction mixture was filtered and the filter cake was dried under reduced pressure to give title product (160 g, 94% yield).1H NMR (400 MHz, DMSO-d6) δ = 10.87 (s, 1H), 7.82 – 7.63 (m, 2H), 7.56 (s, 1H), 7.39 (t, J = 8.0 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.03 – 6.77 (m, 2H).
[00814] Step 2 – (E)-6-chloro-3-(3-chloro-2-fluorobenzylidene)indolin-2-one. (3E)-6-chloro-3-[(3-chloro-2-fluoro-phenyl)methylene]indolin-2-one (50 g, 162 mmol), (5R,6S)-5,6-diphenylmorpholin-2-one (49.3 g, 194 mmol, CAS# 282735-66-4), and cyclohexanone (31.8 g, 324 mmol, 33.6 mL) were dissolved in THF (75 mL) and toluene (750 mL) and 140 ºC for 12 hours. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=8/1 to 5/1) to give the title compound (160 g 97% purity).1H NMR (400 MHz, DMSO-d6) δ = 10.79 (s, 1H), 7.95 ( t, J = 6.8 Hz, 1H), 7.45 – 7.37 (m, 1H), 7.33 – 7.20 (m, 4H), 7.18 – 7.09 (m, 4H), 7.07 – 6.98 (m, 2H), 6.86 – 6.75 (m, 3H), 6.66 (dd, J = 2.0, 8.4 Hz, 1H), 6.35 (d, J = 8.4 Hz, 1H), 5.44 (d, J = 11.2 Hz, 1H), 4.90 (d, J = 2.8 Hz, 1H), 4.58 (d, J = 11.2 Hz, 1H), 2.39 (d, J = 12.8 Hz, 1H), 2.24 – 2.09 (m, 1H), 1.42 – 1.18 (m, 4H), 1.10 – 0.78 (m, 1H).
[00815] Step 3 – (3’S,4’R,7’R,8’S,8a’R)-6”-chloro-8′-(3-chloro-2-fluorophenyl)-3′,4′-diphenyl-3′,4′,8′,8a’-tetrahydro-1’H-dispiro[cyclohexane-1,6′-pyrrolo[2,1-c][1,4]oxazine-7′,3”-indoline]-1′,2”-dione. H2SO4 (9.07 g, 92.5 mmol, 4.93 mL) was added to a solution of intermediate (E)-6-chloro-3-(3-chloro-2-fluorobenzylidene)indolin-2-one (9.0 g, 14.03 mmol) dissolved in MeOH (70 mL) and the resulting solution was heated to 50 °C for 5 hours. On completion, the reaction mixture was cooled to 0 °C and slowly neutralized with a solution of saturated sodium bicarbonate. The aqueous solution was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate, filtered, concentrated to give the residue. The residue was purified by reverse phase flash [ACN/(0.1% FA in water), 0% to 90% ] to give title compound (7.0 g 84.2% purity).1H NMR (400 MHz, DMSO-d6) δ = 7.74 – 7.68 (m, 1H), 7.57 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 7.2 Hz, 4H), 7.25 (d, J = 7.6 Hz, 6H), 7.19 – 7.11 (m, 6H), 7.10 – 6.98 (m, 4H), 6.94 – 6.88 (m, 1H), 6.65 – 6.58 (m, 1H), 5.39 – 5.27 (m, 1H), 4.89 – 4.75 (m, 1H), 4.42 -4.29 (m, 2H), 4.04 (q, J = 6.8 Hz, 1H), 3.63 – 3.53 (m, 2H), 3.40 (s, 3H), 2.22 – 2.12 (m, 1H), 2.05 – 1.94 (m, 3H), 1.40 – 1.32 (m, 2H), 1.28 – 1.13 (m, 3H).
[00816] Step 4 – Methyl (3’R,4’S,5’R)-6”-chloro-4′-(3-chloro-2-fluorophenyl)-1′-((1R,2S)-2-hydroxy-1,2-diphenylethyl)-2”-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3”-indoline]-5′-carboxylate. The resulting intermediate (3’S,4’R,7’R,8’S,8a’R)-6”-chloro-8′-(3-chloro-2-fluorophenyl)-3′,4′-diphenyl-3′,4′,8′,8a’-tetrahydro-1’H-dispiro[cyclohexane-1,6′-pyrrolo[2,1-c][1,4]oxazine-7′,3”-indoline]-1′,2”-dione (7.0 g, 10.3 mmol) was dissolved in ACN (78 mL), then CAN (11.3 g, 20.7 mmol) was added, followed by the addition of H2O (78 mL). The reaction was stirred at 25 °C for 30 min. On completion, the reaction mixture was quenched by adding the mixture to a cold saturated aqueous NaHCO3 solution (50 mL). The aqueous layer was extracted with ethyl acetate (20 mL x 3). The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=50/1 to 5/1) to give title compound (1.58 g, 31% purity). LC-MS (ESI+) m/z 477.2 (M+H)+.
[00817] Step 5 – (3’R,4’S,5’R)-6”-chloro-4′-(3-chloro-2-fluorophenyl)-2”-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3”-indoline]-5′-carboxylic acid. Methyl (3’R,4’S,5’R)-6”-chloro-4′-(3-chloro-2-fluorophenyl)-1′-((1R,2S)-2-hydroxy-1,2-diphenylethyl)-2”-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3”-indoline]-5′-carboxylate (2.00 g, 4.19 mmol) was dissolved in THF (14 mL) and LiOH.H2O (527 mg, 12.5 mmol) was added followed by water (14 mL) and MeOH (2 mL) and the reaction was stirred at 25 °C for 15 min. On completion, water (20 mL) was added and the reaction was slowly neutralized with 2M HCl and the suspension was stirred for 15 min. The resulting precipitate was filtered, washed with water to give title compound (1.50 g, 70% yield).1H NMR (400 MHz, DMSO-d6) δ = 10.75 – 10.57 (m, 1H), 10.55 (s, 1H), 7.61 – 7.54 (m, 1H), 7.50 – 7.44 (m, 1H), 7.41 – 7.34 (m, 1H), 7.18 – 7.12 (m, 1H),
7.08 – 7.02 (m, 1H), 6.72 – 6.66 (m, 1H), 4.72 – 4.65 (m, 1H), 4.54 – 4.47 (m, 1H), 3.18 – 3.15 (m, 1H), 2.22 – 2.13 (m, 1H), 1.83 – 1.70 (m, 2H), 1.64 – 1.52 (m, 3H), 1.51 – 1.43 (m, 2H), 1.42 – 1.34 (m, 1H), 1.04 – 0.92 (m, 1H), 0.89 – 0.77 (m, 1H). LC-MS (ESI+) m/z 463.2 (M+H)+.
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References
- Mdm2 degraders and uses thereofPublication Number:WO-2023049790-A2Priority Date:2021-09-22
- Mdm2 degraders and uses thereofPublication Number:US-2024025878-A1Priority Date:2020-03-19
- Mdm2 degraders and uses thereofPublication Number:WO-2021188948-A1Priority Date:2020-03-19
- Methods of treating cancerPublication Number:WO-2023114933-A1Priority Date:2021-12-15
- Methods of treating cancerPublication Number:US-2023233546-A1Priority Date:2021-12-15
- Methods of treating cancerPublication Number:CN-118574613-APriority Date:2021-12-15
- Methods of treating cancerPublication Number:EP-4447959-A1Priority Date:2021-12-15
- Mdm2 degraders and uses thereofPublication Number:EP-4405359-A2Priority Date:2021-09-22
- Mdm2 degraders and uses thereofPublication Number:WO-2025096262-A1Priority Date:2023-11-01
- Mdm2 degraders and uses thereofPublication Number:WO-2024197219-A1Priority Date:2023-03-22
- Mdm2 degraders and uses thereofPublication Number:WO-2024197216-A2Priority Date:2023-03-22
- Mdm2 degraders and uses thereofPublication Number:US-2025352535-A1Priority Date:2022-06-06
- Mdm2 degraders and uses thereofPublication Number:WO-2023239697-A1Priority Date:2022-06-06
///////////////////seldegamadlin, anax labs, E3 ubiquitin-protein ligase Mdm2 (Hdm2) degrader, antineoplastic, KT 253, KT-253, VNP2BV6KGL
#seldegamadlin, #anax labs, #E3 ubiquitin-protein ligase Mdm2 (Hdm2) degrader, #antineoplastic, #KT 253, #KT-253, #VNP2BV6KGL
Secutrelvir
Secutrelvir
CAS 2996148-73-1
MF C23H16Cl2F3N5O2 MW522.3 g/mol
2-[5-(3-chloro-4-fluorophenyl)-3-(5-chloro-3-pyridinyl)-6-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)-2,4-dioxopyrimidin-1-yl]acetonitrile
2-(5-(3-chloro-4-fluorophenyl)-3-(5-chloropyridin-3-yl)-6-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetonitrile
[5-(3-chloro-4-fluorophenyl)-3-(5-chloropyridin-3-yl)-6-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl]acetonitrile
protease inhibitor, antiviral, S-892216, S 892216, FMV68MJ8XK
Secutrelvir (also known by its developmental code S-892216) is an advanced, next-generation oral antiviral drug developed by the pharmaceutical company Shionogi. It functions as a potent SARS-CoV-2 3C-like protease (3CLpro / \(M^{\text{pro}}\)) inhibitor designed primarily for the treatment of COVID-19.
As of August 2026, the drug has entered late-stage development, with Shionogi moving into Phase 3 clinical trials to assess its efficacy and safety in patients.
Key Properties & Advantages
Unlike first-generation COVID-19 antivirals, secutrelvir was structurally optimized to address the limitations of existing treatments like Paxlovid (nirmatrelvir/ritonavir) and Shionogi’s own Xocova (ensitrelvir).
- No CYP Booster Required: Secutrelvir offers 100% oral bioavailability without needing a pharmacokinetic booster like ritonavir. This dramatically reduces the risk of severe drug-drug interactions that complicate Paxlovid prescriptions.
- Overcoming Viral Resistance: In laboratory assays, the compound demonstrates zero cross-resistance to viral mutants that have grown resistant to nirmatrelvir or ensitrelvir (such as those carrying E166V or M49L mutations).
- High Off-Target Selectivity: It features high selectivity (>15,000-fold) over human proteases, ensuring it specifically targets viral replication without disrupting normal human cellular functions.
- Broad Spectrum (Pan- β-CoV): The compound maintains high potency against a wide range of SARS-CoV-2 variants—including newer strains like Omicron JN.1—as well as other coronaviruses like SARS-CoV and MERS-CoV.
Mechanism of Action
Secutrelvir relies on a structure-based design incorporating a nitrile warhead. It enters the catalytic active site of the virus’s main protease (\(M^{\text{pro}}\)) and forms a reversible covalent bond with the catalytic amino acid residue cysteine C145. By binding to this pocket, it halts the protease from cutting viral polyproteins, effectively stopping viral replication in its tracks.
[Secutrelvir (Nitrile Warhead)] │ ▼ (Reversible Covalent Binding) [Cysteine C145 of 3CLpro] ──► Blocked Protease Activity ──► Viral Replication Stopped
Clinical Evaluation Status
- Pharmacokinetics: Clinical pharmacology data released by Shionogi Medical demonstrated excellent safety, high tolerability, and no clinically relevant food effects, meaning the drug can be taken with or without food.
- Phase 3 Trials (NCT07743580 / NCT07746544): Late-stage double-blind, placebo-controlled interventional studies are assessing the drug in symptomatic, non-hospitalized COVID-19 patients who are at risk of progressing to severe illness. To qualify for the trials, patients must receive the drug within 72 hours of symptom onset
- A Study of Secutrelvir in Participants With Coronavirus Disease 2019 (COVID-19) Who Are at High Risk for Progression to Severe DiseaseCTID:NCT07743580Phase:Phase 3Status:RecruitingDate:2026-08-25
- Study of Secutrelvir in Participants With COVID-19CTID:NCT07746544Phase:Phase 3Status:Not yet recruitingDate:2026-08-05
- A Study of S-892216 in Participants With COVID-19CTID:NCT06928051Phase:Phase 2Status:CompletedDate:2025-09-30
- A Drug-drug Interaction Study of S-892216 Coadministered With Carbamazepime to Healthy Adult ParticipantsCTID:NCT06751017Phase:Phase 1Status:CompletedDate:2025-03-11
Syn
https://patentscope.wipo.int/search/en/detail.jsf?docId=US451712998&_cid=P20-MTTHQ4-21870-1
Example 6
Synthesis of Compound (I-077)
Step 1 Synthesis of Compound (I-077)
| 1H-NMR (CDCl 3) δ: 2.75 (4H, t, J=12.0 Hz), 4.02 (4H, s), 4.74 (2H, s), 7.16-7.18 (2H, m), 7.32-7.35 (1H, m), 7.65 (1H, t, J=2.1 Hz), 8.43 (1H, d, J=2.3 Hz), 8.61 (1H, d, J=2.3 Hz). |
PAT
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References
Uracil derivatives having virus replication inhibitory activity and pharmaceutical composition comprising the samePublication Number:
US-2025092056-A1Priority Date:2022-04-08
////secutrelvir, anax labs, protease inhibitor, antiviral, S-892216, S 892216, FMV68MJ8XK
#secutrelvir, #anax labs, #protease inhibitor, #antiviral, #S-892216, #S 892216, #FMV68MJ8XK
Rugocrixan
Rugocrixan
CAS911715-90-7
MF C19H25N5OS2, MF 403.6 g/mol
(2R)-2-[[2-amino-5-[(1S)-1-phenylethyl]sulfanyl-[1,3]thiazolo[4,5-d]pyrimidin-7-yl]amino]-4-methylpentan-1-ol
(R)-2-((2-Amino-5-(((S)-1-phenylethyl)thio)thiazolo[4,5-d]pyrimidin-7-yl)amino)-4-methylpentan-1-ol
(2R)-2-[(2-amino-5-{[(1S)-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol
CX3C chemokine receptor 1 (CX3CR1) antagonist, antiinflammatory, KAND567, AZD8797, KAND 567, AZD 8797, S9Y83SS7PQ
Rugocrixan (also known by its developmental codes KAND567 and AZD8797) is a first-in-class, orally active small molecule drug candidate developed by Novakand Pharma (formerly Kancera). It acts as a potent, non-competitive allosteric antagonist of the CX3CR1 receptor, which is commonly referred to as the fractalkine receptor. By blocking this specific pathway, the drug prevents hyperinflammation and inhibits the proliferation and DNA repair mechanisms of certain cancer cells.
KAND567, a small molecule, blocks the fractaline (CX3CL1) receptor, which mediates the immune system response to inflammation. Because COVID-19 involves cytotoxic cells associated with this pathway, KAND567 is currently being tested as a treatment for those with the illness.
KAND567, a small molecule, blocks the fractaline (CX3CL1) receptor, which mediates the immune system response to inflammation. Because COVID-19 involves cytotoxic cells associated with this pathway, KAND567 is currently being tested as a treatment for those with the illness.
Key Clinical Developments and Therapeutic Focus
Originally acquired from AstraZeneca, the drug has advanced into multiple Phase II clinical trials. Novakand Pharma transitioned its core business strategy to focus heavily on orphan drug designations for niche, treatment-resistant conditions. Its primary areas of investigation include:
- Ovarian Cancer: Evaluated in the Phase IIa “KANDOVA” clinical trial for patients with treatment-resistant ovarian cancer. It functions by suppressing DNA repair in tumor cells, which enhances the effectiveness of platinum-based chemotherapy and drives the cancer cells into programmed cell death.
- Hematological Cancers: In preclinical studies alongside institutions like the Karolinska Institutet, rugocrixan has demonstrated a capability to block the unwanted growth-promoting effects of immune cells on advanced blood cancers, such as chronic lymphocytic leukemia (CLL).
- Cardioprotection: Investigated via the “FRACTAL” Phase IIa trial in patients suffering from acute myocardial infarction (STEMI) undergoing angioplasty. The drug met its safety endpoints and showed signals of protecting heart tissue by reducing myocardial bleeding and the risk of thrombosis.
Companion Prodrug
Novakand Pharma is also developing a second-generation, water-soluble phosphate prodrug named fosrugocrixan (KAND145). Once administered, fosrugocrixan is metabolized into the active form of rugocrixan, offering enhanced product properties for intravenous or alternative delivery methods.
Because rugocrixan targets a brand-new pharmacological pathway, the World Health Organization (WHO) assigned it a unique suffix stem, establishing it as the international nomenclature standard for this entire new class of CX3CR1 antagonists
- A Study to Evaluate the Safety of KAND567, in Combination With Carboplatin Therapy, in Women With Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal CancerCTID:NCT06087289Phase:Phase 1/Phase 2Status:CompletedDate:2025-06-08
- Safety, Tolerability and Pharmacokinetics After Continuous Infusion of KAND567CTID:NCT06030375Phase:Phase 1Status:CompletedDate:2023-09-11
- KAND567 Versus Placebo in Subjects Hospitalized With COVID-19CTID:NCT06012565Phase:Phase 2Status:TerminatedDate:2023-08-25
- KANDOVA – A two-part Phase Ib/IIa study to evaluate the safety and tolerability of KAND567, in combination with carboplatin therapy, and to determine the Recommended Phase II Dose (RPIID) of KAND567. An open-label, multicenter dose escalation study with an expansion cohort in women with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer.EudraCT:2022-002792-11Phase:Phase 2Status:Trial now transitionedDate:2023-03-27
- KAND567 Versus Placebo in Subjects Hospitalized with COVID-19. A Phase II, Randomized, 2-Arm Parallel-Group, Double-blind Study to Evaluate Efficacy, Safety, Tolerability, and Pharmacokinetics.EudraCT:2020-002322-85Phase:Phase 2Status:Completed, Prematurely EndedDate:2020-07-02
SYN
PAT
WO 2006/107258.
PAT
EP1869056
https://patentscope.wipo.int/search/en/detail.jsf?docId=EP14857146&_cid=P20-MTP714-98881-1
Example 12
(2R)-2-[{2-Amino-5-[(1-phenylethyl)thio][1,3]thiazolo[4,5-d]pyrimidin-7-yl}(methyl)amino]-4-methylpentan-1-ol
a) (2R)-2-[[2-Amino-5-(benzylthio)[1,3]thiazolo[4,5-d]pyrimidin-7-yl](methyl)amino]-4-methylpentan-1-ol
[0097] 5-(Benzylthio)-7-chloro[1,3]thiazolo[4,5 -d]pyrimidin-2-amine (1.5 g, 4.86 mmol), DIPEA (691 mg, 5.35 mmol) and ( R)- N-methylleucinol (956 mg, 7.29 mmol) were mixed in NMP (7.5 mL). The resulting solution was stirred at 110 °C under a nitrogen atmosphere for 2 days. After cooling to room temperature the reaction mixture was poured onto ice. The resulting yellow precipitate was collected by filtration, washed with water and dried in vacuo. The crude product was purified by flash column chromatography on silica (DCM:EtOAc 50:50 to 0:100) to give 1.42 g (72% yield) of the title compound as a yellow solid.
1H NMR (DMSO-d 6) 7.97 (br s, 2H), 7.40 (m, 2H), 7.28 (m, 2H), 7.21 (m, 1H), 4.73 (dd, 1H), 4.64 (br s, 1H), 4.32 (br s, 2H), 3.52-3.37 (m, 2H), 3.00 (s, 3H), 1.55-1.35 (m, 2H), 1.27 (m, 1H), 0.88 (d, 3H), 0.80 (d, 3H);
MS (ESI +) m/ z 404 [M+H] +.
PAT
RU0002411245
PAT
WO2019219771
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019219771&_cid=P20-MTP714-98881-2
(2R)-2-[(2-amino-5-{[(1S)-1- phenylethyl]thio}[1 ,3]thiazolo[4,5-c/]pyrimidin-7-yl)amino]-4-methylpentan-1-ol is known to be a potent antagonist .
3.4 Preparation of (2R)-2-r(2-amino-5-(r(1 S)-1 -phenylethyllthio)ri ,3lthiazolor4,5-c/1Pyrimidin-7-yl)aminol-4-methylpentan-1 -ol.xHCI (5)
.xHCI
Compound 4 (1 .852 g, 5.74 mmol), DIPEA (1.1 12 g, 8.61 mmol) and D-leucinol (1.008 g, 8.61 mmmol) were dissolved in NMP (12 ml.) and the mixture was stirred at 120 °C in a sealed pyrex tube (start: 17:40).
HPLC after 15.5 h: ca. 98% conversion
HPLC after 19.5 h: >99% conversion
Work up: Ice water was poured into the mixture. Initially a solid was formed, but at the end of the addition the solid collapsed to a dark brown oil. EtOAc (50 ml.) was added and the phases were separated. The aqueous phase was extracted with EtOAc (2×25 ml_), and the combined organic phases were washed with water (8 ml_), sat. NaHC03 (3×8 ml_), water (8 ml.) and brine (8 ml_), dried over MgS04, filtered and evaporated. Dried in vacuum to yield 2.697 g of crude material as a brown oil. HPLC purity: ca. 92%. The oil was dissolved in MEK (ca. 18 mL) and cone. HCI (12.5 M, 574 pL, 7.18 mmol) was added. There was no spontaneous precipitation of the HCI salt. The mixture was gently stirred at RT and after ca. 20 min precipitation occurred. The mixture was stirred gently for 2.5 h and the solid was isolated by filtration on a P3 sintered glass filter. The solid was washed with three portions of MEK and was then dried in vacuum at 60 °C for 2.5 days. Yield (batch 1 ): 1 .224 g (48.5%) of the product as hydrochloride salt.
HPLC purity: 99.0% (basic method);
97.4% (acidic method).
A substantial amount of solids passed through the filter into the filtrate. The solids were isolated by centrifugation and the supernatant was removed by pipette. The solid was washed with two portions (ca. 2×5 mL) of MEK. After the last supernatant was removed the product was dried in vacuum at 60 °C for 2.5 days. Yield (batch 2): 324 mg (12.8%) of the product as hydrochloride salt.
HPLC purity: 99.0% (basic method);
97.5% (acidic method).
Combined yield: 1.548 g (61 .3%)
Both batches contain ca. 0.07% DMF (w/w). The DMF was already present in the starting material.
Further purification of the combined batches
The two batches of compound 5 were combined (1.338 g, 3.041 mmol) in a 50 mL roundbottomed flask and water (6 mL) was added followed by 2M NaOH (1.6 mL, 3.2 mmol). The mixture was stirred and EtOAc (40 mL) was added. An additional 0.5 mL (1 mmol) 2M NaOH was added during stirring. After 15 min all of the solids were dissolved and the phases were separated. The pH of the aqueous phase was measured with a pH stick =>pH=7. More 2M NaOH (0.4 mL, 0.8 mmol) was added to the aqueous phase resulting in a pH of 10. The aq. phase was extracted with EtOAc (25 mL) and the phases were separated. The combined organic phases were dried over Na2S04, filtered and evaporated to yield the free base as a crystalline beige solid. The free base was dissolved in MEK (15 mL) and HCI (37%, 12.5 M, 255 pL, 3.19 mmol) was added during stirring. A white precipitate was immediately formed. The mixture was stirred gently for 2 h and the solid was collected by filtration on a P4 sintered glass filter. The solids were washed with MEK (5 mL) and dried in vacuum at 60 °C for 3 h. Yield: 1.187 g (89% based on the unpurified material) of 99% pure product as a white solid. 1H NMR (600 MHz, CD30D) d ppm 7.49 (d, J=7.3 Hz, 2 H) 7.37 (t, J=7.6 Hz, 2 H) 7.27 – 7.32 (m, 1 H) 5.23 (q, J=7.0 Hz, 1 H) 4.60 – 4.70 (m, 1 H) 3.55 (d, J=5.5 Hz, 2 H) 1.83 (d, J=7.3 Hz, 3 H) 1.67 – 1.76 (m, 1 H) 1.58 -1.65 (m, 1 H) 1.48 – 1.54 (m, 1 H) 1.00 (d, J=6.7 Hz, 3 H) 0.98 (d,J=6.7 Hz, 3 H). MS (ESI+) m/z 404 [M+H]+
The diasteromeric ratio of the final product reflects the enantiomeric ratio of the starting material (compound 1 ), which was 99.7% (S).
1H NMR: The spectrum looks very pure. Trace amounts of DMF were, however, detected.
Comparative Example 4 – Process scale two-step procedure for the synthesis of 6-amino-2-{r(1S)-1-phenylethvnsulfanyl)pyrimidin-4-ol (1 )
Step 1 Step 2
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References
- Novel 5-substituted 7-amino-[1,3]thiazolo[4,5-d]pyrimidine derivativesPublication Number:CA-2604017-CPriority Date:2005-04-06Grant Date:2012-03-06
- Novel 5-substituted 7-amino [1,3] thiazolo [4,5-D] pyrimidine derivativesPublication Number:JP-5165553-B2Priority Date:2005-04-06Grant Date:2013-03-21
- Novel 5,7-Disubstituted [1,3]Thiazolo[4,5-D]Pyrimidin-2(3H)-One Derivatives 794Publication Number:US-2009124637-A1Priority Date:2005-04-06
- New derivatives of 5, 7-disubstituted [1, 3] thiazolo[4, 5-d] pyrimidine-2(3h)-onePublication Number:RU-2411245-C9Priority Date:2005-04-06Grant Date:2011-05-27
- Novel 5-Substituted 7-Amino-[1,3]Thiazolo[4,5-D]Pyrimidine Derivatives 793Publication Number:US-2008214578-A1Priority Date:2005-04-06
- NEW DERIVATIVES OF 5-SUBSTITUTED 7-AMINO-[1, 3] THIAZOLO [4, 5-d]PYRIMIDINEPublication Number:RU-2419623-C2Priority Date:2005-04-06Grant Date:2011-05-27
- Novel 5,7-disubstituted [1,3] thiazolo [4,5-D] pyrimidin-2 (3H) -one derivativesPublication Number:JP-2008535834-APriority Date:2005-04-06
//////////rugocrixan, anax labs, CX3C chemokine receptor 1 (CX3CR1) antagonist, antiinflammatory, KAND567, AZD8797, KAND 567, AZD 8797, S9Y83SS7PQ
#rugocrixan, #anax labs, #CX3C chemokine receptor 1 (CX3CR1) antagonist, #antiinflammatory, #KAND567, #AZD8797, #KAND 567, #AZD 8797, #S9Y83SS7PQ
DR ANTHONY MELVIN CRASTO
ORGANIC SPECTROSCOPY
