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 cyclopenta$d$𝑑pyridazine 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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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

[WO2021030711]

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

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=2A0850BB19B29C599F589233A4E61A49.wapp2nB?docId=WO2026064728&_cid=P21-MU6C38-37561-1

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.

Step 2. To a solution of N4-(3-chloro-2-fluoro-phenyl)-7-[2-[(1S,5R)-3-methyl-3-azabicyclo[3.1.0]hexan-1-yl]ethynyl]quinazoline-4,6-diamine (4.00 g, 9.81 mmol) and triethylamine (2.98 g, 29.4 mmol) in dichloromethane (70 mL) was added a solution of (E)-4-bromobut-2-enoyl chloride (3.60 g, 19.6 mmol) in dichloromethane (15 mL) dropwise at 0° C. and the mixture was stirred at 0° C. for 10 min. On completion, the reaction mixture was concentrated under vacuum to give (E)-4-bromo-N-(4-((3-chloro-2-fluorophenyl)amino)-7-4(1R,5S)-3-methyl-3-azabicyclo[3.1.0]hexan-1-yl)ethynyl)quinazolin-6-yl)but-2-enamide (5.44 g, crude) as a yellow solid, which was used for next step directly. m/z ES+ [M+H] + 556.0

Step 3. A mixture of (E)-4-bromo-N-[4-(3-chloro-2-fluoro-anilino)-7-[2-[(1S,5R)-3-methyl-3-azabicyclo[3.1.0]hexan-1-yl]ethynyl]quinazolin-6-yl]but-2-enamide (5.44 g, 9.80 mmol), morpholine (1.71 g, 19.6 mmol), triethylamine (992 mg, 9.80 mmol) in dichloromethane (1.5 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 25° C. for 12 hrs under N 2 atmosphere. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by reverse phase flash [acetonitrile/(0.1% formic acid in water), 0% to 90%] to give 2.8 g crude product. Then it was purified by Prep-HPLC [column: Waters Xbridge BEH C18 250*50 mm*10 um; mobile phase: [water (0.05% ammonium hydroxide v/v)-acetonitrile]; B %: 35%-55%, 22 min] to give 2.2 g crude product. Then the crude product was triturated with EA/petroleum ether=5/1 (200 mL) twice to give (E)-N-[4-(3-chloro-2-fluoro-anilino)-7-[2-[(1S,5R)-3-methyl-3-azabicyclo[3.1.0]hexan-1-yl]ethynyl]quinazolin-6-yl]-4-morpholino-but-2-enamide (1.84 g, 33% yield) as a yellow solid. m/z ES+ [M+H] + 561.3; 1H NMR (400 MHz, DMSO-d 6) δ 10.06 (s, 1H), 9.78 (s, 1H), 8.67 (s, 1H), 8.48 (s, 1H), 7.80 (s, 1H), 7.50 (s, 2H), 7.29 (t, J=7.6 Hz, 1H), 6.81 (td, J=5.6, 15.6 Hz, 1H), 6.45 (d, J=15.6 Hz, 1H), 3.65-3.60 (m, 4H), 3.17 (d, J=5.2 Hz, 2H), 3.11 (d, J=8.4 Hz, 1H), 2.93 (d, J=9.0 Hz, 1H), 2.46-2.38 (m, 6H), 2.26 (s, 3H), 1.98-1.90 (m, 1H), 1.38 (t, J=4.4 Hz, 1H), 1.03 (dd, J=4.0, 8.0 Hz, 1H).

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References

1.  "Silevertinib". AdisInsight. Springer Nature Switzerland AG. Retrieved 5 July 2026.
2.  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]

Figure 1. Schematic of radiosynthesis using two-step two-pot pathway.

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

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=7C55DB9EE5B2E59D667F3571B796AE12.wapp1nB?docId=US249082034&_cid=P11-MU3HKD-32540-1

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

1.  CID 54255856 from PubChem
2.  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.
3.  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.
4.  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.
5.  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.
6.  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.
7.  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.
8.  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.
9.  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.
10.  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.
11.  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
12.  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.
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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