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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
Romaciclib
Romaciclib
CAS 1609522-33-9
MWC15H18Br2N4 MF414.14 g/mol
6,7-dibromo-5-methyl-2-piperazin-1-yl-1,3-diazatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraene
7,8-dibromo-9-methyl-2-(piperazin-1-yl)-5,6-dihydro-4Himidazo[4,5,1-ij]quinoline
cyclin-dependent kinase inhibitor, antineoplastic, RVU-120, SEL-120, SEL120-34, SEL120-34A, RVU 120, SEL 120, ORPHAN DRUG, 6LGR0RYY5Q
Romaciclib is an investigational new drug being evaluated by Ryvu Therapeutics for the treatment of acute myeloid leukaemia (AML). It is a dual inhibitor of CDK8 and CDK19.[1][2][3]
Romaciclib is an investigational, orally bioavailable small-molecule dual inhibitor of cyclin-dependent kinases 8 and 19 (CDK8 and CDK19), being developed by Ryvu Therapeutics for the treatment of hematologic malignancies such as acute myeloid leukemia (AML) and myelofibrosis.
Mechanism of Action
- Targeted Inhibition: Romaciclib selectively targets CDK8 and CDK19 to disrupt oncogenic transcription programs essential for cancer cell survival while minimizing off-target effects.
- Oral Administration: As an oral pill, it offers convenience and supports long-term therapy compliance compared to intravenous treatments.
- Combination Potential: Preclinical and clinical evaluations show it helps overcome resistance mechanisms—such as restoring sensitivity to venetoclax (VEN) in relapsed/refractory AML—and exhibits synergistic activity with JAK inhibitors in myelofibrosis models.
Clinical Development
- Acute Myeloid Leukemia (AML): Evaluated in the Phase II RIVER-81 study in combination with venetoclax, showing encouraging anti-leukemic activity and durable responses in patients with relapsed or refractory disease.
- Myelofibrosis (MF): Investigated as a monotherapy or combined with ruxolitinib in the Phase II POTAMI-61 trial
- RVU120 Rollover StudyCTID:NCT06987058Phase:Phase 2Status:Enrolling by invitationDate:2026-07-28
- RVU120 in Patients With Intermediate or High-risk, Primary or Secondary MyelofibrosisCTID:NCT06397313Phase:Phase 2Status:RecruitingDate:2025-09-23
- RVU120 for Treatment of Anemia in Patients With Lower-risk Myelodysplastic NeoplasmsCTID:NCT06243458Phase:Phase 2Status:Active, not recruitingDate:2025-05-22
- Safety and Efficacy of RVU120 for Treatment of Relapsed/Refractory AMLCTID:NCT06268574Phase:Phase 2Status:Active, not recruitingDate:2025-05-08
- Safety and Efficacy of RVU120 Combined With Venetoclax for Treatment of Relapsed/Refractory AMLCTID:NCT06191263Phase:Phase 2Status:RecruitingDate:2025-04-13
- OriginatorSelvita
- DeveloperRyvu Therapeutics
- ClassAntineoplastics; Halogenated hydrocarbons; Imidazoles; Piperazines; Quinolones; Small molecules
- Mechanism of ActionCyclin dependent kinase 19 inhibitors; Cyclin-dependent kinase 8 inhibitors
- Orphan Drug StatusYes – Acute myeloid leukaemia
- Phase IIAcute myeloid leukaemia; Myelodysplastic syndromes; Myelofibrosis; Solid tumours
- Phase IMedulloblastoma
- 11 Jun 2026The US FDA reactivates the IND, enabling the initiation of the expansion cohort of phase II RIVER-81 trial in Acute myeloid leukaemia at the recommended dose of 150 mg once daily (QD)
- 11 Jun 2026Updated efficacy data from a phase II RIVER-81 trial in Acute myeloid leukaemia released by Ryvu Therapeutics
- 21 May 2026Ryvu Therapeutics plans a phase II ROVER-01 trial for Acute myeloid leukaemia, Myelodysplastic syndromes and Solid tumours in the Poland and Spain (NCT06987058)
Romaciclib is an orally bioavailable inhibitor of cyclin-dependent kinases 8 and 19 (CDK8/19), with potential antineoplastic and chemoprotective activities. Upon oral administration, romaciclib targets, binds to and inhibits the activity of CDK8/19, which prevents activation of CDK8/19-mediated oncogenic signaling pathways, blocks selective transcription of various tumor-promoting genes, and inhibits proliferation of CDK8/19-overexpressing tumor cells. CDK8/19, serine/threonine kinases involved in the regulation of the cell cycle, are overexpressed in certain cancer cell types and play key roles in tumor cell proliferation.
PAT
US20150274726
https://patentscope.wipo.int/search/en/detail.jsf?docId=US152387110&_cid=P10-MTMCT7-27170-1
7,8-dibromo-9-methyl-2-(piperazin-1-yl)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline,
PAT
- Substituted tricyclic benzimidazoles as kinase inhibitorsPublication Number:EP-2917217-B1Priority Date:2012-11-08Grant Date:2017-03-08
- Substituted tricyclic benzimidazoles as kinase inhibitorsPublication Number:CN-104903321-APriority Date:2012-11-08
- SUBSTITUTED TRICYCLIC BENZIMIDAZOLS, THEIR USES, AND PHARMACEUTICAL COMPOSITIONPublication Number:BR-112015010019-B1Priority Date:2012-11-08
- Substituted tricyclic benzimidazoles as kinase inhibitorsPublication Number:US-9745299-B2Priority Date:2012-11-08Grant Date:2017-08-29
- Substituted tricyclic benzimidazoles as kinase inhibitorsPublication Number:US-2015274726-A1Priority Date:2012-11-08
- C. novyi for the treatment of solid tumors in humansPublication Number:EP-3730146-B1Priority Date:2013-03-29Grant Date:2022-05-04
- Clostridium nodarii for the treatment of human solid tumorsPublication Number:CN-105451750-BPriority Date:2013-03-29Grant Date:2023-03-10
- C. novyi for the treatment of solid tumors in humansPublication Number:EP-4108248-A1Priority Date:2013-03-29
- C. novyi for the treatment of solid tumors in non-human animalsPublication Number:US-12433920-B2Priority Date:2013-03-29Grant Date:2025-10-07
- C. novyi for the treatment of solid tumors in humansPublication Number:EP-4108248-B1Priority Date:2013-03-29Grant Date:2025-09-17
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References
- “Romaciclib – Ryvu Therapeutics”. AdisInsight. Springer Nature Switzerland AG.
- Rajendra A, Yee KW (April 2026). “Clinical development of a CDK8/19 kinase inhibitor for acute myeloid leukemia”. Expert Opinion on Investigational Drugs. 35 (4): 253–256. doi:10.1080/13543784.2026.2656430. PMID 41931045.
- Pakulska U, Obacz M, Woźnicki J, Wiklik K, Chakraborty S, Micek M, et al. (January 2026). “Romaciclib, a CDK8/CDK19 inhibitor, can overcome venetoclax resistance through a combinatorial strategy”. bioRxiv 10.64898/2025.12.16.693978.
- Cyclin-Dependent Kinase 8: A New Hope in Targeted Cancer Therapy?Publication Name:Journal of Medicinal ChemistryPublication Date:2017-12-21PMID:29266937DOI:10.1021/acs.jmedchem.7b00901
- SEL120-34A is a novel CDK8 inhibitor active in AML cells with high levels of serine phosphorylation of STAT1 and STAT5 transactivation domainsPublication Name:OncotargetPublication Date:2017-04-04PMCID:PMC5464911PMID:28422713DOI:10.18632/oncotarget.16810
- Discovery of a Novel and Potent Cyclin-Dependent Kinase 8/19 (CDK8/19) Inhibitor for the Treatment of CancerPublication Name:Journal of Medicinal ChemistryPublication Date:2024-05-01PMID:38690856DOI:10.1021/acs.jmedchem.4c00248
- Discovery of a novel oral type Ⅰ CDK8 inhibitor against acute myeloid leukemiaPublication Name:European Journal of Medicinal ChemistryPublication Date:2023-05-05PMID:36889252DOI:10.1016/j.ejmech.2023.115214
- Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Inhibitors of CDK8 for the Treatment of CancerPublication Name:Journal of Medicinal ChemistryPublication Date:2023-04-07PMID:37029334DOI:10.1021/acs.jmedchem.2c01718
- From Structure Modification to Drug Launch: A Systematic Review of the Ongoing Development of Cyclin-Dependent Kinase Inhibitors for Multiple Cancer TherapyPublication Name:Journal of Medicinal ChemistryPublication Date:2022-04-29PMID:35485642DOI:10.1021/acs.jmedchem.1c02064
- A comprehensive insight on the recent development of Cyclic Dependent Kinase inhibitors as anticancer agentsPublication Name:European Journal of Medicinal ChemistryPublication Date:2020-10-01PMID:32707525DOI:10.1016/j.ejmech.2020.112571
//////////romaciclib, ANAX LABS, cyclin-dependent kinase inhibitor, antineoplastic, RVU-120, SEL-120, SEL120-34, SEL120-34A, RVU 120, SEL 120, ORPHAN DRUG, 6LGR0RYY5Q
#romaciclib, #ANAX LABS, #cyclin-dependent kinase inhibitor, #antineoplastic, #RVU-120, #SEL-120, #SEL120-34, #SEL120-34A, #RVU 120, #SEL 120, #ORPHAN DRUG, #6LGR0RYY5Q
Rocavorexant
Rocavorexant
CAS 2115665-09-1
MFC18H19F3N8O MW420.39
N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)-N-[(2S)-1-{[5-(trifluoromethyl)pyrazin-2-yl]amino}propan-2-yl]pyridine-2-
carboxamide
orexin-1 receptor antagonist, INDV-2000, C4X-3256, INDV 2000, C4X 3256,
Rocavorexant (developmental codes INDV-2000 and C4X-3256) is a potent, selective, oral orexin-1 receptor (OX₁R) antagonist originally developed to treat opioid use disorder and other substance-related disorders.
Clinical development of the drug has been suspended. In April 2026, Indivior announced that it would not advance the drug internally for opioid use disorder because the Phase 2 proof-of-concept trial failed to meet its primary endpoint of “no treatment failure”.
Key Drug Profile
- Mechanism of Action: Highly selective antagonist for the human orexin-1 receptor (pIC50 of 9.1) compared to the orexin-2 receptor (pIC50 of 6.0).
- Target Pathway: Aims at relapse-related neural circuitry, anxiety modulation, and stress-induced addictive behaviors.
- Chemical Formula: C₁₈H₁₉F₃N₈O.
- Current Status: Suspended internally by Indivior, which is actively seeking external business development and out-licensing opportunities due to positive secondary data regarding abstinence and safet
Rocavorexant (INNTooltip International Nonproprietary Name; developmental code names C4X-3256 and INDV-2000) is an orexin OX1 receptor antagonist which is under development for the treatment of opioid-related disorders and other substance-related disorders.[1][2][3][4] It is taken orally.[1] The drug is under development by C4X Discovery and/or Indivior.[1][2] As of May 2026, development for all indications has been suspended.[1] The drug has reached phase 2 clinical trials for opioid-related disorders and phase 1 trials for substance-related disorders.[1][2][4]
Rocavorexant is the antagonist for orexin-1 receptor with pIC50 of 9.1 for human OX1 (while pIC50 for human OX2 is 6.0).
1. Primary patent — most important reference
WO2017129829A1 — “Therapeutic compounds”
Inventor: Barrie P. Martin
Priority: 29 January 2016
Publication: 3 August 2017
WO2017129829A1 – Google Patents
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017129829&_cid=P12-MTJHA5-23107-1
This patent explicitly identifies Rocavorexant as:
N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)-N-[(2S)-1-{[5-(trifluoromethyl)pyrazin-2-yl]amino}propan-2-yl]pyridine-2-carboxamide, and provides its preparation as Example 1.
The patent is particularly useful because it contains large-scale examples, not merely milligram medicinal-chemistry experiments.
Preparation of A/,6-dimethyl-3-(2H-1 ,2,3-triazol-2-yl)-A/-r(2S)-1 -f r5-(trifluoro methyl)pyrazin-2-yllamino)propan-2-yllpyridine-2-carboxamide (Example 1 , Scheme 3)
To a stirred solution of Int 11 (0.58 g, 2.1 mmol) in THF (2 mL) was added DIPEA (1 .0 mL, 5.8 mmol) followed by 2-chloro-5-(trifluoromethyl)pyrazine (0.39 g, 2.1 mmol) and the mixture was heated at 70 °C for 4 hrs. The reaction mixture was allowed to cool to ambient temperature and allowed to stand over the weekend. The reaction mixture was heated at 70 °C for a further 4 hrs with stirring and allowed to cool to ambient temperature. The reaction mixture was evaporated in vacuo. The residue was purified by preparative HPLC (Column: Waters Xbridge C18 (10 μιτι, 30 x 100 mm). Conditions: Water + 0.2% ammonium hydroxide [Eluent A]; MeCN + 0.2% ammonium hydroxide [Eluent B]. Gradient: 10 to 95% B) and then lyophilised to give title compound as a white solid (0.32 g)
LCMS (Method C): Two peaks at 4.20 and 4.39 min, 421 [M+H]+
1 H NMR (500 MHz, d4-MeOH) δ 8.38 (d, 0.15 H), 8.34 (bs, 0.15 H), 8.24 (d, 0.85 H), 8.03 (bs, 0.85 H), 7.99 (s, 0.30 H), 7.97 (s, 1 .70 H), 7.85 (bs, 1 .00 H), 7.57 (d, 0.15 H),
7.41 (d, 0.85 H), 4.98 (m, 0.15 H), 4.06 (bm, 0.85 H), 3.50 (d, 0.15 H), 3.47 (d, 0.85 H),
3.42 (d, 0.85 H), 3.39 (d, 0.15 H), 3.05 (s, 2.55 H), 2.83 (s, 0.45 H), 2.65 (s, 0.45 H), 2.45 (bs, 2.55 H), 1 .38 (d, 0.45 H), 1 .07 (bs, 2.55 H). Preparation of A/,6-dimethyl-3-(2H-1 ,2,3-triazol-2-yl)-A/-r(2S)-1 -U5-(trifluoro methyl)pyrimidin-2-yllamino)propan-2-yllpyridine-2-carboxamide
US patent
US 11,130,746 B2 — Therapeutic compounds
This is especially relevant because its claims specifically cover processes for preparing the compounds, including:
Route A: reaction of the pyridine acid/lithium salt with an amide-coupling reagent and the chiral amine.
Route B: reaction of
N-[(2S)-1-aminopropan-2-yl]-N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide
with an appropriate heteroaryl leaving-group compound in the presence of a base.
The patent specifically lists thionyl chloride among the coupling reagents and DIPEA as an appropriate base for the heteroaryl substitution route.
Other patent-family references
- US 10,696,654 B2
- US 11,130,746 B2
- US 11,753,398
- US 12,441,709 B2
The later US family documents retain the Rocavorexant compound/process disclosure. For example, US10696654B2 reproduces the Example 1 synthesis and the Int 14 preparation.
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References
- “Rocavorexant”. AdisInsight. 12 May 2026. Retrieved 5 June 2026.
- “Delving into the Latest Updates on Rocavorexant with Synapse”. Synapse. 9 May 2026. Retrieved 5 June 2026.
- Raymond JS, Vareed RD, Peters J, James MH (October 2025). “Found in translation: orexin receptor antagonism for the treatment of opioid use disorder”. Translational Psychiatry. 15 (1) 432. doi:10.1038/s41398-025-03571-5. PMC 12552597. PMID 41136352.
- Lorente JS, Sokolov AV, Ferguson G, Schiöth HB, Hauser AS, Gloriam DE (June 2025). “GPCR drug discovery: new agents, targets and indications”. Nature Reviews. Drug Discovery. 24 (6): 458–479. doi:10.1038/s41573-025-01139-y. PMID 40033110.
 | |
| Clinical data | |
|---|---|
| Other names | C4X-3256; C4X3256; INDV-2000; INDV2000 |
| Routes of administration | Oral[1] |
| Drug class | Orexin OX1 receptor antagonist |
| Identifiers | |
| IUPAC name | |
| CAS Number | 2115665-09-1 |
| PubChem CID | 130295635 |
| ChemSpider | 133325612 |
| UNII | 8RJN30TJM6 |
| KEGG | D13324 |
| Chemical and physical data | |
| Formula | C18H19F3N8O |
| Molar mass | 420.400 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| SMILES | |
| InChI | |
////rocavorexant, anax labs, orexin-1 receptor antagonist, INDV-2000, C4X-3256, INDV 2000, C4X 3256,
#rocavorexant, #anax labs, #orexin-1 receptor antagonist, #INDV-2000, #C4X-3256, #INDV 2000, #C4X 3256,
Rizavasertib
Rizavasertib
CAS 552325-16-3
MF C24H23N5O MW397.5 g/mol
(2S)-1-(1H-indol-3-yl)-3-[[5-(3-methyl-2H-indazol-5-yl)-3-pyridinyl]oxy]propan-2-amine
(2S)-1-(1H-indol-3-yl)-3-{[5-(3-methyl-1H-indazol-5-yl)pyridin-3-yl]oxy}propan-2-amine
serine/threonine kinase inhibitor, A-443654, A 443654, A443654, Q4UG565ZYH
Rizavasertib was a drug candidate originally developed by Abbott (now AbbVie).[1][2][3][4] It is a pan akt Inhibitor.[5] It is now used as an akt inhibitor tool compound.[6]
Rizavasertib (also known by its developmental code A-443654) is a potent, small-molecule pan-Akt (protein kinase B) inhibitor originally developed by Abbott Laboratories (now AbbVie). It acts as a highly effective research tool compound used to investigate cellular signaling pathways, particularly in oncology and tumor cell biology
- Mechanism of Action: It is an ATP-competitive inhibitor that targets all three Akt isoforms (Akt1, Akt2, and Akt3) with equal intracellular potency, showing an inhibition constant (\(\text{K}_{i}\)) of 160 pM.
Key Biological & Research Effects
- Pathway Modulation: It induces a rapid, paradoxical phosphorylation of Akt at the Ser-473 residue, occurring independently of mTORC1 inhibition.
- Mitotic Regulation: The compound interferes with normal cell division (mitotic progression) by regulating the expression of Aurora A kinase.
- Oncology Models: In preclinical testing, it has demonstrated an ability to prolong survival in animal models of intracranial glioma and shows potential therapeutic relevance against both primary and drug-resistant T-cell acute lymphoblastic leukemia (T-ALL).
Current Status
Rizavasertib’s highest global development status remains Preclinical. It is not approved for human use or clinical medical treatment and is sold exclusively by chemical suppliers like MedChemExpress as an analytical reference standard or reagent for qualitative, quantitative, and methodological research (such as HPLC, GC, and mass spectrometry).
PAT
US20030199511 and literature Bioorganic & Medicinal Chemistry 2006, 14, 6832–6846, a method for preparing A-443654 is disclosed,
PAT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2003051366&_cid=P11-MTGMSN-41566-1
PAT
https://patentscope.wipo.int/search/en/detail.jsf?docId=US40155124&_cid=P11-MTGN0W-48129-1
SIMILAR
EXAMPLE 191
(1R)-1-(1H-Indol-3-ylmethyl)-2-[5-(3-methyl-1H-indazol-5-yl)-pyridin-3-yloxy]-ethylamine
PAT
CN104610229
https://patentscope.wipo.int/search/en/detail.jsf?docId=CN133679262&_cid=P11-MTGNFX-58461-1
Example 4: Preparation of Compound 6
| Compound 5 (104 g, 178.9 mmol) and methanol (620 ml, 6V) were added to a 1 L three-necked flask. A 4M HCl/ethyl acetate (130 ml) solution was added dropwise at a temperature below 25 °C. The reaction was allowed to proceed overnight. The reaction was monitored by TLC until the starting material was completely reacted. The mixture was concentrated and drained to dryness using an oil pump to obtain 104 g of crude product. Water (900 ml) and ethyl acetate (1350 ml) were added, and the mixture was stirred until the system was clear. The mixture was allowed to stand, and the organic layer was separated. The aqueous phase was extracted once again with ethyl acetate (500 ml). The organic phases were combined, and water (180 ml) was added. Most of the ethyl acetate was concentrated until solid began to precipitate. The mixture was cooled in an ice bath, stirred, and allowed to crystallize for 30 min. The mixture was filtered, and the filter cake was dried to obtain a white solid (57.9 g, yield 86%, purity 98.3%). |
| 1H NMR(CD 3 OD,500MHz):δppm 8.45(s,1H),8.25(brs,1H),7.98(s,1H),7.61(m,4H),7.37(s,1H),7.16(s,1H),7.10(m,1H),7.00(m,1H),4.18(m,1H),4.03(m,1H),3.56(m,1H),3.10(m,1H),3.00(m,1H),2.62(s,3H)；ESI/MS:m/z＝398(M+H)+. |
Pat
- Kinase inhibitorsPublication Number:US-6831175-B2Priority Date:2001-12-13Grant Date:2004-12-14
- 3- (Phenyl-alkoxy) -5- (phenyl) -pyridine derivatives and related compounds as kinase inhibitors for cancer treatmentPublication Number:JP-2005516927-APriority Date:2001-12-13
- Methods of treating muscular wasting diseases using NF-KB activation inhibitorsPublication Number:US-9173920-B2Priority Date:2006-03-15Grant Date:2015-11-03
- Kinase inhibitorsPublication Number:US-2003187026-A1Priority Date:2001-12-13
- 3-(phenyl-alkoxy)-5-(phenyl)-pyridine derivatives and related compounds as kinase inhibitors for the treatment of cancerPublication Number:CA-2470214-A1Priority Date:2001-12-13
- Kinase inhibitorsPublication Number:US-2003199511-A1Priority Date:2001-12-13
- 3-(phenyl-alkoxy)-5-(phenyl)-pyridine derivatives and related compounds as kinase inhibitors for the treatment of cancerPublication Number:WO-03051366-A2Priority Date:2001-12-13
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References
- “Research programme: protein kinase inhibitors – AbbVie”. AdisInsight. Springer Nature Switzerland AG.
- Luo Y, Shoemaker AR, Liu X, Woods KW, Thomas SA, de Jong R, et al. (June 2005). “Potent and selective inhibitors of Akt kinases slow the progress of tumors in vivo”. Molecular Cancer Therapeutics. 4 (6): 977–986. doi:10.1158/1535-7163.MCT-05-0005. PMID 15956255.
- Gandelman M, Dansithong W, Kales SC, Paul S, Maag G, Aoyama E, et al. (October 2021). “The AKT modulator A-443654 reduces α-synuclein expression and normalizes ER stress and autophagy”. The Journal of Biological Chemistry. 297 (4) 101191. doi:10.1016/j.jbc.2021.101191. PMC 8482485. PMID 34520759.
- Ming J, Jin S, Liu Z, Yang K, Shi M, Niu Y (October 2025). “Imidacloprid contributes to bladder cancer progression: preliminary evidence based on network toxicology, machine learning and molecular docking”. BMC Pharmacology & Toxicology. 26 (1) 180. doi:10.1186/s40360-025-01016-9. PMC 12577002. PMID 41168844.
- Crowell JA, Steele VE, Fay JR (August 2007). “Targeting the AKT protein kinase for cancer chemoprevention”. Molecular Cancer Therapeutics. 6 (8): 2139–2148. doi:10.1158/1535-7163.MCT-07-0120. PMID 17699713.
- Garcia-Echeverria C, Sellers WR (September 2008). “Drug discovery approaches targeting the PI3K/Akt pathway in cancer”. Oncogene. 27 (41): 5511–5526. doi:10.1038/onc.2008.246. PMID 18794885.
 | |
| Clinical data | |
|---|---|
| Other names | A-443654 |
| Identifiers | |
| IUPAC name | |
| CAS Number | 552325-16-3 |
| PubChem CID | 10172943 |
| IUPHAR/BPS | 8204 |
| DrugBank | DB08073 |
| ChemSpider | 8348448 |
| UNII | Q4UG565ZYH |
| ChEBI | CHEBI:91351 |
| ChEMBL | ChEMBL379300 |
| PDB ligand | L20 (PDBe, RCSB PDB) |
| CompTox Dashboard (EPA) | DTXSID20436347  |
| Chemical and physical data | |
| Formula | C24H23N5O |
| Molar mass | 397.482 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| SMILES | |
| InChI | |
/////////rizavasertib, anax labs, serine/threonine kinase inhibitor, A-443654, A 443654, A443654, Q4UG565ZYH
#rizavasertib, #anax labs, #serine/threonine kinase inhibitor, #A-443654, #A 443654, #A443654, #Q4UG565ZYH
Rusfertide
Rusfertide
MF
C114H181N27O28S2 MW 2442.0 g/mol
isovaleryl-Asp-Thr-His-Phe-Pro-Cys(1)-Ile-Lys(2)-Phe-Glu-Pro-Arg-Ser-Lys-Gly-Cys(1)-Lys-NH2.palmitoyl-Glu(2)-OH
(2S)-5-[4-[(3S,6S,9S,12S,15R,20R,26S,29S,32S,35S)-26-(4-aminobutyl)-6-benzyl-12-[(2S)-butan-2-yl]-32-(3-carbamimidamidopropyl)-3-(2-carboxyethyl)-15-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-3-carboxy-2-(3-methylbutanoylamino)propanoyl]amino]-3-hydroxybutanoyl]amino]-3-(1H-imidazol-4-yl)propanoyl]amino]-3-phenylpropanoyl]pyrrolidine-2-carbonyl]amino]-20-[[(2S)-1,6-diamino-1-oxohexan-2-yl]carbamoyl]-29-(hydroxymethyl)-2,5,8,11,14,22,25,28,31,34-decaoxo-17,18-dithia-1,4,7,10,13,21,24,27,30,33-decazabicyclo[33.3.0]octatriacontan-9-yl]butylamino]-2-(hexadecanoylamino)-5-oxopentanoic acid
{Asp(N-(3-methyl-1-oxobutyl))}-Thr-His-Phe-Pro-Cys-Ile-{Lys(γGlu-C16 acid)}-Phe-Glu-Pro-Arg-Ser-Lys-Gly-Cys-Lys-NH2 (disulfide bridge: Cys6-Cys16)
Mimrylo, APPROVALS 2026, FDA 2026, XM71MYX0IQ, PTG-300FB, PTG-300, TAK 121,
To treat erythrocytosis in adults with polycythemia vera
Rusfertide is a peptide mimetic of natural hepcidin, which targets and degrades ferroportin, reduces serum iron and transferrin-saturation, and thus regulates the production of red blood cells. Rusfertide ameliorates the polycythemia vera, β-thalassemia and hereditary hemochromatosis.
Rusfertide is an injectable peptide mimetic of hepcidin (hepcidin antimicrobial peptide; HAMP; putative liver tumor regressor; PLTR; liver-expressed antimicrobial peptide 1; LEAP-1) with potential use in the treatment of iron deficiency anemia and iron overload secondary to hematologic disorders. Upon administration, rusfertide mimics endogenous hepcidin, a protein primarily produced in hepatocytes, and increases hepcidin levels. As hepcidin plays a key role in the homeostasis of systemic iron, rusfertide may serve to normalize iron levels. Low levels of endogenous hepcidin are associated with iron overload secondary to excessive absorption of iron as seen in beta thalassemia and paradoxically with iron deficiency anemia.
Rusfertide, sold under the brand name Mimrylo, is a medication developed by Protagonist Therapeutics in partnership with Takeda for the treatment of polycythemia vera (PV).[1][2][3]
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References
 | |
| Clinical data | |
|---|---|
| Trade names | Mimrylo |
| Other names | PTG-300; TAK-121 |
| Identifiers | |
| CAS Number | 1628323-80-7 |
| PubChem CID | 155884410 |
| DrugBank | DB17724 |
| ChemSpider | 129955617 |
| UNII | XM71MYX0IQ |
| KEGG | D12064 |
| ChEMBL | ChEMBL4650507 |
| Chemical and physical data | |
| Formula | C114H181N27O28S2 |
| Molar mass | 2441.98 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| SMILES | |
| InChI | |
References
- “Rusfertide – Protagonist Therapeutics”. AdisInsight. Springer Nature Switzerland AG.
- Kremyanskaya M, Ginzburg YZ, Hoffman R (March 2026). “Modulators of the hepcidin pathway in polycythemia vera and myelofibrosis”. Blood. 147 (12): 1278–1288. doi:10.1182/blood.2025028643. PMID 41100735.
- “Protagonist and Takeda Announce ASCO Plenary Presentation Highlighting Full 32-Week Results from Phase 3 VERIFY Study of Rusfertide, Showing Reductions in Phlebotomy, Improved Hematocrit Control in Polycythemia Vera”. Takeda.
//////rusfertide, anax labs, Mimrylo, APPROVALS 2026, FDA 2026, XM71MYX0IQ, PTG-300FB, PTG 300, TAK 121,
#rusfertide, #anax labs, #Mimrylo, #APPROVALS 2026, #FDA 2026, #XM71MYX0IQ, #PTG-300FB, #PTG-300, #TAK 121,
Brepocitinib
Brepocitinib
CAS 1883299-62-4
MF C18H21F2N7O MW389.4 g/mol
8/27/2026, APPROVALS 2026, FDA 2026, Lisraya, PF 06700841, 3X8387Q25N, PF-06700841
[(1S)-2,2-difluorocyclopropyl]-[(1R,5S)-3-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]methanone
- [(1S)-2,2-difluorocyclopropyl]-[(1S,5R)-3-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]methanone
- Methanone, ((1S)-2,2-difluorocyclopropyl)(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-4-pyrimidinyl)-3,8-diazabicyclo(3.2.1)oct-8-yl)-
- ((1S)-2,2-difluorocyclopropyl)-((1S,5R)-3-(2-((1-methylpyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo(3.2.1)octan-8-yl)methanone
To treat dermatomyositis in adults
Brepocitinib (brand name Lisraya) is an oral, once-daily dual TYK2/JAK1 inhibitor approved by the FDA for treating dermatomyositis in adults.
Developed by Roivant (via its subsidiary Priovant), it is the first oral targeted therapy indicated to manage this rare, debilitating autoimmune condition. Brepocitinib, sold under the brand name Lisraya, is a drug which acts as a dual inhibitor of JAK1 and TYK2, and was developed for the treatment of plaque psoriasis.[1][2][3][4] It is used for the treatment of dermatomyositis.
Brepocitinib is an orally available, selective inhibitor of non-receptor tyrosine-protein kinase TYK2 (tyrosine kinase 2) and tyrosine-protein kinase JAK1 (Janus kinase 1; JAK1) with potential immunomodulatory and anti-inflammatory activities. Upon oral administration, brepocitinib selectively binds to and inhibits the activation of TYK2 and JAK1, thereby disrupting TYK2 and JAK-1-dependent cytokine signaling. This may reduce inflammatory responses and prevent inflammation-induced damage caused by certain immunological diseases. TYK2 and JAK-1 are members of the Janus kinase family of non-receptor tyrosine kinases and are involved in signaling pathways affecting hematopoiesis, immunity and inflammation.
SYN
Dual Inhibition of TYK2 and JAK1 for the Treatment of Autoimmune Diseases: Discovery of ((S)-2,2-Difluorocyclopropyl)((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (PF-06700841)
By: Fensome, Andrew ; et al
Journal of Medicinal Chemistry (2018), 61(19), 8597-8612
SYN
Preparation of aminopyrimidinyl derivatives as inhibitors of JAK kinases useful in therapy of diseases
Assignee: Pfizer Inc.
Inventors: Fensome, Andrew; et al
World Intellectual Property Organization
Patent#WO2016027195 A1
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016027195&_cid=P11-MTCC5U-40903-1
SYN
https://www.sciencedirect.com/science/article/abs/pii/S0223523423008152
SYN
PAT
https://patentscope.wipo.int/search/en/detail.jsf?docId=US159751917&_cid=P11-MTCCDC-53135-1
Examples 7 and 8
[(1S)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone and [(1R)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone
Peak 1: Example 7
[(1S)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone
PAT
- New compounds for the inhibition of angiogenesis and use of thereofPublication Number:AU-2005223356-A1Priority Date:2004-03-24
- Compositions and methods of use for modified release minoxidilPublication Number:US-2025325546-A1
- Aminopyrimidinyl compoundsPublication Number:US-10980815-B2Priority Date:2014-08-21Grant Date:2021-04-20
- Aminopyrimidinyl compounds as JAK inhibitorsPublication Number:MD-4800-C1Priority Date:2014-08-21
- Aminopyrimidinyl compoundsPublication Number:US-2020330477-A1Priority Date:2014-08-21
- Aminopyrimidinyl compoundsPublication Number:US-11197867-B2Priority Date:2014-08-21Grant Date:2021-12-14
- Aminopyrimidinyl compoundsPublication Number:TW-201609706-APriority Date:2014-08-21
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References
References
- Fensome A, Ambler CM, Arnold E, Banker ME, Brown MF, Chrencik J, et al. (October 2018). “Dual Inhibition of TYK2 and JAK1 for the Treatment of Autoimmune Diseases: Discovery of (( S)-2,2-Difluorocyclopropyl)((1 R,5 S)-3-(2-((1-methyl-1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (PF-06700841)”. Journal of Medicinal Chemistry. 61 (19): 8597–8612. doi:10.1021/acs.jmedchem.8b00917. PMID 30113844.
- Forman SB, Pariser DM, Poulin Y, Vincent MS, Gilbert SA, Kieras EM, et al. (December 2020). “TYK2/JAK1 Inhibitor PF-06700841 in Patients with Plaque Psoriasis: Phase IIa, Randomized, Double-Blind, Placebo-Controlled Trial”. The Journal of Investigative Dermatology. 140 (12): 2359–2370.e5. doi:10.1016/j.jid.2020.03.962. PMID 32311398.
- Martin G (February 2023). “Novel Therapies in Plaque Psoriasis: A Review of Tyrosine Kinase 2 Inhibitors”. Dermatology and Therapy. 13 (2): 417–435. doi:10.1007/s13555-022-00878-9. PMC 9884727. PMID 36592300.
- Caso F, Costa L, Triggianese P, Maione F, Bertolini N, Vastarella M, et al. (May 2023). “Recent developments for new investigational JAK inhibitors in psoriatic arthritis”. Expert Opinion on Investigational Drugs. 32 (5): 361–371. doi:10.1080/13543784.2023.2207737. PMID 37096862.
 | |
| Clinical data | |
|---|---|
| Trade names | Lisraya |
| Other names | PF-06700841 |
| Identifiers | |
| IUPAC name | |
| CAS Number | 1883299-62-4 |
| PubChem CID | 118878093 |
| DrugBank | DB15003 |
| ChemSpider | 72380129 |
| UNII | 3X8387Q25N |
| ChEMBL | ChEMBL4297477 |
| Chemical and physical data | |
| Formula | C18H21F2N7O |
| Molar mass | 389.411 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| SMILES | |
| InChI | |
///////////brepocitinib, anax labs, APPROVALS 2026, FDA 2026, Lisraya, PF 06700841, 3X8387Q25N, PF-06700841, dermatomyositis
#brepocitinib, #anax labs, #APPROVALS 2026, #FDA 2026, #Lisraya, #PF 06700841, #3X8387Q25N, #PF-06700841, #dermatomyositis
DR ANTHONY MELVIN CRASTO
ORGANIC SPECTROSCOPY
New Drug Approvals 
