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Wednesday, 23 September 2026

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 / PhaseTreatment TypeResults & 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 TherapyOngoing. 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 namesSolengepras; CVN-424; CVN424
Routes of
administration		Oral[1]
Drug classGPR6 inverse agonist
Identifiers
IUPAC name
CAS Number2254706-21-1
PubChem CID137359492
DrugBankDB18958
ChemSpider114869317
UNIIXO01711URG
KEGGD12980
ChEMBLChEMBL4778540
Chemical and physical data
FormulaC24H29F2N5O3
Molar mass473.525 g·mol−1
3D model (JSmol)Interactive image
SMILES
InChI
  1. "Solengepras". AdisInsight. 21 October 2024. Retrieved 25 February 2025.
  2. "Delving into the Latest Updates on CVN-424 with Synapse". Synapse. 5 February 2025. Retrieved 25 February 2025.
  3. Gros P, Garcia LA, Fox SH (2025). "Experimental Therapeutics in Parkinson's Disease". Neurologic Clinics. 43 (2): 399–426. doi:10.1016/j.ncl.2024.12.013. PMID 40185528.
  4. Brice NL, Schiffer HH, Monenschein H, Mulligan VJ, Page K, Powell J, et al. (June 2021). "Development of CVN424: A Selective and Novel GPR6 Inverse Agonist Effective in Models of Parkinson Disease". The Journal of Pharmacology and Experimental Therapeutics. 377 (3): 407–416. doi:10.1124/jpet.120.000438. PMID 33795395.

External links

////////////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

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Monday, 21 September 2026

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

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

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References

  1.  Hampsey E, Perkins A, Young AH (April 2023). "BNC210: an investigational α7-nicotinic acetylcholine receptor modulator for the treatment of anxiety disorders". Expert Opin Investig Drugs. 32 (4): 277–282. doi:10.1080/13543784.2023.2192922. PMID 36927202.
  2. Andriambeloson, E., Wagner, S., Huyard, B., Sleebs, B., Quasi, N., Bui, C., ... & Street, I. (2007, September). BNC210: A Novel Compound with Potent Anxiolytic Activity. In Behavioral Pharmacology (Vol. 18, pp. S16–S16). https://neurofit.com/im-posters/2008-ebps-bnc210.pdf
  3. https://cdn.who.int/media/docs/default-source/international-nonproprietary-names-(inn)/pl132.pdf#page=198 soclenicantum soclenicant 6-[(2,3-dihydro-1H-inden-2-yl)amino]-1-ethyl-3-(morpholine4-carbonyl)-1,8-naphthyridin-4(1H)-one nicotinic acetylcholine receptor negative allosteric modulator, anxiolytic
  4. "BNC 210". AdisInsight. 30 December 2024. Retrieved 22 February 2025.
  5. "Delving into the Latest Updates on BNC-210 with Synapse". Synapse. 23 January 2025. Retrieved 22 February 2025.
  6. O'Connor SM, Sleebs BE, Street IP, Flynn BL, Baell JB, Coles C, Quazi N, Paul D, Poiraud E, Huyard B, Wagner S, Andriambeloson E, de Souza EB (March 2024). "BNC210, a negative allosteric modulator of the alpha 7 nicotinic acetylcholine receptor, demonstrates anxiolytic- and antidepressant-like effects in rodents". Neuropharmacology. 246 109836. doi:10.1016/j.neuropharm.2024.109836. hdl:11343/348285. PMID 38185416.
  7. "CID 24772165". PubChem. Retrieved 5 January 2026.
  8. Bionomics Limited Press Release (2019-11-04). "Bionomics Announces Fast Track Designation Granted by U.S. FDA to BNC210 Development Program for the Treatment of PTSD". BusinessWire. Retrieved 2020-09-09.
Clinical data
Other namesBNC210; BNC-210; IW2143; IW-2143
Routes of
administration		Oral
Drug classα7-Nicotinic acetylcholine receptor negative allosteric modulator
ATC codeNone
Legal status
Legal statusInvestigational
Pharmacokinetic data
Bioavailability69.4% (rat)[1][2]
Protein binding70–88%[1][2]
Elimination half-life6.2 hours (rat)[1][2]
Identifiers
IUPAC name
CAS Number1020634-41-6 check
PubChem CID24772165
UNIIQP49AY37OY
KEGGD13360
Chemical and physical data
FormulaC24H26N4O3
Molar mass418.497 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

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Saturday, 19 September 2026

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 cyclopentadd𝑑pyridazine 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

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=B04410250978C4E0B0F323AD027AC8B8.wapp1nB?docId=US457344867&_cid=P11-MU96YW-11754-1

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

 4.62 kg of compound a was completely dissolved in 25.0 L of glacial acetic acid and added to a 100 L reaction kettle, 3300 g of benzoic anhydride was added, and the mixture was reacted at room temperature for about 4 hours with stirring turned on. The reaction was monitored by TLC (n-hexane/ethyl acetate=5/1) until compound a disappeared, then 2722 g of anhydrous sodium acetate was additionally added and the temperature was increased to 120° C. for a reaction under stirring for about 18 hours.
      The reaction solution was cooled to 60-65° C., and concentrated under reduced pressure to remove most of the acetic acid. After the concentration was completed, 10 L of anhydrous ethanol was added to the residue and uniformly mixed. Then the mixed solution was slowly added to 250 L of water, while maintaining the rapid stirring, and a large amount of solid precipitated during the addition, and stirring was continued for about 0.5 hours after the addition, followed by centrifugation. The filter cake was washed with purified water (20 L×2) to give compound b in 100% yield, which went directly to the next step.
      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).
      LCMS m/z=433.1 [M+1]+

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.
      The temperature was reduced to 25° C., 30 L of water was added, the pH was adjusted to 8-9 with an ammonium chloride solid, and 35.0 L of ethyl acetate was added and stirred. The solution was phase-separated. The aqueous phase was extracted with ethyl acetate (15.0 L×2). The organic phases were combined and washed with a 5% aqueous sodium chloride solution (25 L×2). The organic phase was dried over 3.0 Kg of anhydrous sodium sulfate, filtered, and concentrated until no significant distillate flowed out, so as to obtain a crude product.
      The crude product and 7.0 L of an aqueous 10% dioxane solution were heated for complete dissolution, cooled to room temperature, and crystallized with stirring for about 16 hours, followed by filtration to obtain a wet product, which was repeated purified twice and dried under vacuum at 50° C. for about 12 hours to give 1507 g of compound c.
      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).
      LCMS m/z=329.0 [M+1]+

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:

      Instrument: MG III preparative SFC; column: Whelk 01 (S, S), 300× 50 mm I.D., 10 um; mobile phase: A: CO2, B: methanol; gradient: B 40%; flow rate: 200 mL/min; back pressure: 100 bar; column temperature: 38° C.; wavelength: 220 nm; period: 4.5 min; sample preparation: the racemate was dissolved in methanol/dichloromethane to achieve 50 mg/ml; and injection: 17 ml/injection.

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).
      LCMS m/z=329.1 [M+1]+

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).
      LCMS m/z=329.0 [M+1]+

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%.
      After the completion of the reaction, the temperature was controlled to 10+5° C., and 30.0 kg of purified water was added to the reaction kettle. After the addition, the temperature was controlled at 10+5° C. with stirring continued for 1 hour, followed by filtration, and the cake was washed with 3.0 kg of purified water. The filter cake and 12.6 kg of anhydrous ethanol were added to a 100 L reaction kettle, heated to 50±5° C., and stirred for about 1 hour. The mixture was cooled to 20±5° C., stirred for 0.5 hours and filtered, and the filter cake was washed once with 1.26 kg of anhydrous ethanol.
      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).
      LCMS m/z=496.1 [M+1]+

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

 To a 100 L reaction kettle, 12.40 kg of N,N-dimethylacetamide, 2.6269 kg of compound e and 0.54 kg of sodium acetate were added with stirring. After the addition, the temperature was increased and the internal temperature was maintained at 115+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 e was determined by HPLC to be≤1.0%.
      After the completion of the reaction, the temperature was reduced to 60±5° C., 0.788 kg of purified water was added to the reaction solution, and after the addition, the reaction solution was filtered while still hot and quickly added to 13.66 kg of purified water, and the temperature was lowered to 10+5° C. After filtration, the filter cake was added to 20 L of dimethyl sulfoxide and warmed for complete dissolution. 800 L of acetone was added and stirred for 0.5 to 1 h, and then filtered. The filter cake was dried at 55+5° C. with vacuum≤−0.07 MPa for about 20 hours to give the amorphous form of the compound of formula (I), weighing 1.56 kg.
      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).
      LCMS m/z=450.0 [M+1]+.

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