Imofinostat

 

Imofinostat

CAS 1338320-94-7

MF C17H16N2O4S MW 344.4 g/mol

• 3-(1-(Benzenesulfonyl)-2,3-dihydro-1H-indol-5-yl)-N-hydroxyacrylamide
• (E)-3-[1-(benzenesulfonyl)-2,3-dihydroindol-5-yl]-N-hydroxyprop-2-enamide

(2E)-3-[1-(benzenesulfonyl)-2,3-dihydro-1H-indol-5-yl]-N-hydroxyprop2-enamide
histone deacetylase inhibitor, antineoplastic, ABT-301, MPT0E028, ABT 301, MPT0E 028, T65L58FI65

Imofinostat (also known as ABT-301 or MPT0E028) is an orally bioavailable, small-molecule histone deacetylase (HDAC) inhibitor primarily being developed as an innovative precision oncology treatment. Developed by companies like AnBogen Therapeutics and Formosa Pharmaceuticals, it is designed to reactivate tumor suppressor genes that cancer cells have silenced, thereby triggering cancer cell death (apoptosis) and stopping tumor growth.

Mechanism of Action

Imofinostat works through a distinct multi-modality approach to fight cancer cells:

• HDAC Inhibition: It acts as a potent inhibitor of human pan-histone deacetylase enzymes, showing preferential selectivity for Class I HDACs (especially HDAC3). This blocks the deacetylation of histone proteins, causing chromatin to remodel and forcing cancer cells to express tumor-suppressor genes.
• Akt Pathway Targeting: Independent of its epigenetic effects, it can directly target and reduce the activation (phosphorylation) of the Akt protein kinase, a major pathway that cancer cells use to survive and multiply.
• Microenvironment Modulation: Preclinical data shows it alters the tumor microenvironment by converting "cold tumors" (invisible to the immune system) into "hot tumors" by promoting the infiltration of CD8+ cytotoxic T cells.

Current Clinical Status & Indications

Imofinostat is actively moving through clinical trial pipelines, focusing heavily on combination therapies to overcome treatment resistance:

• Colorectal Cancer (CRC): It is currently being evaluated in a global Phase 1/2 clinical trial (NCT07244705). It is combined with the immune checkpoint inhibitor tislelizumab (Tevimbra®) and the anti-angiogenic drug bevacizumab to treat advanced, metastatic colorectal cancer.
• Pancreatic Cancer: Recent data presented at the 2026 American Association for Cancer Research (AACR) Annual Meeting demonstrates that imofinostat disrupts the HDAC3-NRF2 pathway. This action breaks down chemotherapy resistance in highly aggressive KRAS-mutant pancreatic ductal adenocarcinoma, making tumors much more sensitive to treatments like gemcitabine.
• Other Solid Tumors: Phase 1 monotherapy trials have confirmed that the drug possesses a highly competitive safety profile across a broad variety of advanced solid tumors.

Imofinostat is an orally bioavailable N-hydroxyacrylamide-derived inhibitor of both human pan-histone deacetylase (HDAC) enzymes and the serine/threonine protein kinase Akt (protein kinase B), with potential antineoplastic activity. Upon administration, imofinostat selectively binds to and inhibits HDACs, which inhibits deacetylation of histone proteins and leads to the accumulation of highly acetylated histones. This may result in both an induction of chromatin remodeling, and the selective transcription of tumor suppressor genes. This prevents cell division and induces both cell cycle arrest and apoptosis, which may inhibit the proliferation of susceptible tumor cells. In addition, imofinostat inhibits the phosphorylation and activation of Akt, which prevents the activation of downstream signaling pathways, independent of its HDAC inhibitory activity. HDACs, upregulated in many tumor cell types, are a family of enzymes that deacetylate histone proteins. Akt, overexpressed in many tumor cell types, plays a key role in tumor cell proliferation and survival.

Dose-Seeking Study of MPT0E028 in Subjects With Advanced Solid Malignancies Without Standard Treatment

CTID: NCT02350868

Phase: Phase 1

Status: Completed

Date: 2019-04-11

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2011126821&_cid=P11-MQ4LAI-84972-1

COMD 12

Compound 12 was synthesized via the route as shown in Scheme 3 above (reagents and conditions: (a) NaBH₃CN, AcOH; (b) Benzenesulfonyl chloride, 4-methoxybenzenesulfonyl chloride, 3,4-dimethoxybenzenesulfonyl chloride, 4-fluorobenzenesulfonyl chloride, or 4-nitrobenzenesulfonyl chloride, pyridine; (c) L1AIH₄, THF; (d) PDC, MS, CH₂C1₂; f) Ph₃P = CH-COOCH₃, CH₂C1₂; (g) 1M LiOH(aq), dioxane; (h) (i) NH₂OTHP, PyBOP, NEt₃, DMF; (ii) TFA, MeOH; (i) Fe, NH₄C1, Isopropanol, H₂0).

2,3-Dihydro-lH-indole-5-carboxylic acid methyl ester (10): sodium cyanoborohydride (0.16 g, 2.57 mmol) was added to a solution of methyl indole-5-carboxylate (9) (0.30 g, 1.71 mmol) in AcOH (2 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 2 h before it was quenched with water at 0 °C. Concentrated NaOH was added to reach pH=10. The aqueous layer was extracted with CH₂CI₂ (15 mL x 3). The combined organic layer was dried over anhydrous MgS0₄ and concentrated under reduced pressure to give a yellow residue, which was purified by silica gel chromatography (EtOAc: n-hexane = 1 : 2) to afford 10 (0.28 g). 1H NMR (500MHz, CDC1₃): δ 3.06 (t, J= 8.5 Hz, 2H), 3.65 (t, J= 8.5 Hz, 2H), 3.84 (s, 3H), 6.53-6.55 (m, 1H), 7.75-7.76 (m, 2H).

l-Benzenesulfonyl-2,3-dihydro-lH-indole-5-carboxylic acid methyl ester (11): To a solution of 10 (0.28 g, 1.58 mmol) in pyridine (2 mL), benzenesulfonyl chloride (0.40 ml, 3.16 mmol) was added. The reaction mixture was refluxed overnight. The mixture was then purified by silica gel chromatography (EtOAc: n-hexane = 1 : 3) to afford 11 (0.40 g). 1H NMR (500MHz, CDCI₃): δ 2.99 (t, J= 8.6 Hz, 2H), 3.87 (s, 3H), 3.97 (t, J= 8.6 Hz, 2H), 7.45-7.48 (m, 2H), 7.56-7.59 (m, 1H), 7.66 (d, J= 8.5 Hz, 1H), 7.75 (s, 1H), 7.82 (d, J= 7.7 Hz, 2H), 7.90 (d, J= 7.9 Hz, 1H).

(l-Benzenesulfonyl-2,3-dihydro-lH-indol-5-yl)-methanol (12): LAH (0.10 g, 2.52 mmol) was added to a solution of 11 (0.40 g, 1.26 mmol) in THF (10 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 2 h before it was quenched with water and then extracted with CH₂CI₂ (15 mL x 3). The combined organic layer was dried over anhydrous MgS0₄ and concentrated under reduced pressure. The reaction mixture was purified by silica gel chromatography (EtOAc: n-hexane = 1 : 1) to afford 12 (0.24 g). 1H NMR (500MHz, CDC1₃): δ 2.83 (t, J= 8.4 Hz, 2H), 3.92 (t, J= 8.5 Hz, 2H), 4.49 (s, 2H), 7.09 (s, 1H), 7.16 (d, J= 8.2 Hz, 1H), 7.46-7.49 (m, 2H), 7.53 (d, J= 8.2 Hz, 1H), 7.60 (t, J= 7.5 Hz, 1H), 7.76 (d, J= 7.7 Hz, 2H).

l-Benzenesulfonyl-2,3-dihydro-lH-indole-5-carbaldehyde (13): molecular sieves (0.63g) were added to a solution of 12 (0.24 g, 0.83 mmol) in CH₂C1₂ (10 mL), PDC (0.63 g, 1.66 mmol). The mixture was stirred at room temperature overnight before it was filtered through celite. The organic layer was concentrated under reduced pressure then purified by silica gel chromatography (EtOAc: n-hexane = 1 : 2) to afford 13 (0.19 g). 1H NMR (500MHz, CDC1₃): δ 3.05 (t, J= 8.6 Hz, 2H), 4.01 (t, J= 8.7 Hz, 2H), 7.46-7,49 (m, 2H), 7.58-7.62 (m, 2H), 7.71 (d, J= 8.3 Hz, 1H), 7.75 (d, J= 8.3 Hz, 1H), 7.84 (d, J= 7.8 Hz, 2H), 9.85 (s, 1H).

3-(l-Benzenesulfonyl-2,3-dihydro-lH-indol-5-yl)-acrylic acid methyl ester (14): Methyl (triphenylphosphoranylidene) acetate (0.27 g, 0.79 mmol) was added to a solution of 13 (0.19g,

0.66 mmol) in CH₂CI₂ (10 mL). The mixture was stirred at room temperature for 3h before it was

quenched with water and then extracted with CH₂CI₂ (15 mL x 3). The combined organic layer was dried over anhydrous MgS0₄ and concentrated under reduced pressure to give a yellow residue, which was then purified by silica gel chromatography (EtOAc: n-hexane = 1 : 3) to afford 14

(0.20 g).

3-(l-Benzenesulfonyl-2,3-dihydro-lH-indol-5-yl)-acrylic acid (15): 1M LiOH aqueous solution (1.16 ml, 1.16 mmol) was added to a solution of 14 (0.20g, 0.58 mmol) in dioxane

(15 mL). The reaction mixture was stirred at 40 °C overnight before it was concentrated under reduced pressure. The residue was dissolved in water and concentrated HCl was added up to acidic pH to give the precipitation, which was dried by vacuum to afford 15 (0.16 g). 1H NMR (500MHz, CD₃OD): δ 2.92 (t, J= 8.5 Hz, 2H), 3.96 (t, J= 8.5 Hz, 2H), 6.33 (d, J= 15.9 Hz, 1H), 7.38 (s, 1H), 7.41 (d, J= 8.5 Hz, 1H), 7.50-7.53 (m, 2H), 7.55 (d, J= 16.1 Hz, 1H), 7.58-7.64 (m, 2H), 7.82 (d, J = 7.6 Hz, 2H).

3-(l-Benzenesulfonyl-2,3-dihydro-lH-indol-5-yl)-N-hydroxy-acrylamide

(Compound 12): NH₂OTHP (0.05 g, 0.44 mmol) was added to a solution of 15 (0.12 g, 0.37 mmol), PyBOP (0.20 g, 0.39 mmol), triethylamine (0.12 ml, 0.88 mmol) in DMF (1.5 mL). The reaction mixture was stirred at room temperature for 1 h before it was quenched with water, followed by extraction with EtOAc (15 mL x 3). The combined organic layer was dried over anhydrous MgS0₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography (CH₂C1₂: CH3OH = 30 : 1 : l%NH_3(aq)) to give a white solid, which was treated with TFA (1.13 ml, 15.21 mmol) in the presence of CH₃OH (25 mL) and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to give a white residue, which was recrystallized by CH₃OH to afford Compound 12 (0.12 g). 1H NMR (500MHz,

CD₃OD): δ 2.91 (t, J= 8.5 Hz, 2H), 3.96 (t, J= 8.4 Hz, 2H), 6.32 (d, J= 15.8 Hz, 1H), 7.32 (s, 1H), 7.37-7.39 (m, 1H), 7.46 (d, J= 15.7 Hz, 1H), 7.50-7.53 (m, 2H), 7.58-7.64 (m, 2H), 7.82 (d, J= 7.8 Hz, 2H). MS (EI) mlz: 170 (100%), 344 (M⁺, 3.21%). HRMS (EI) for Ci₇Hi₆N₂0₄S (M⁺): calcd, 344.0831; found, 344.0829.

PAT

 US20150368195

https://patentscope.wipo.int/search/en/detail.jsf?docId=US154007904&_cid=P11-MQ4M0P-01888-1

PAT

• Indolyl or indolinyl hydroxamate compoundsPublication Number: US-8846748-B2Priority Date: 2010-03-29Grant Date: 2014-09-30
• Indolyl or indolinyl hydroxamate compoundsPublication Number: US-9598364-B2Priority Date: 2010-03-29Grant Date: 2017-03-21
• Indolyl or indolinyl hydroxamate compoundsPublication Number: WO-2011126821-A2Priority Date: 2010-03-29
• Indolyl or indolinyl hydroxamate compoundsPublication Number: EP-2552887-A2Priority Date: 2010-03-29
• Indolyl or indolinyl hydroxamate compoundsPublication Number: US-2011245315-A1Priority Date: 2010-03-29
• Indolyl or indolinyl hydroxamate compoundsPublication Number: US-2014364477-A1Priority Date: 2010-03-29
• Indolyl or indolinyl hydroxamate compoundsPublication Number: EP-2552887-B1Priority Date: 2010-03-29Grant Date: 2018-10-24

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References

//////////imofinostat, anax labs, histone deacetylase inhibitor, antineoplastic, ABT-301, MPT0E028, ABT 301, MPT0E 028, T65L58FI65

#imofinostat, anax labs, #histone deacetylase inhibitor, #antineoplastic, #ABT-301, #MPT0E028, #ABT 301, #MPT0E 028, #T65L58FI65

Inidascamine

 

Inidascamine

CAS 903884-71-9

MF C12H17N3O2 MW235.28 g/mol

(-)-(2R,3S)-2-amino-3-hydroxy-3-(pyridin-4-yl)-1-(pyrrolidin-1-yl)propan-1-one

(2R,3S)-2-amino-3-hydroxy-3-pyridin-4-yl-1-pyrrolidin-1-ylpropan-1-one

(2R,3S)-2-amino-3-hydroxy-3-(pyridin-4-yl)-1-(pyrrolidin-1-yl)propan-1-one
schizophrenia, 3LW01V88B7, RL 007

Inidascamine (developmental code name RL-007 or FSV7-007) is an experimental, orally administered drug primarily studied for treating Cognitive Impairment Associated with Schizophrenia (CIAS). Developed jointly by Recognify Life Sciences and atai Life Sciences, the molecule targets the underlying neural mechanisms that restrict verbal learning, memory retention, and mental processing speed in schizophrenia patients

Mechanism of Action

The compound is designed to alter the brain's complex excitatory and inhibitory balance to produce pro-cognitive effects. It accomplishes this by interacting with three major neurotransmitter systems simultaneously:

• Cholinergic system: Modulates acetylcholine pathways vital for attention and memory.
• Glutamatergic system: Interacts with NMDA/glutamate receptors to influence synaptic plasticity.
• GABAergic system: Targets \(GABA_{B}\) receptors to stabilize neural transmission.

Clinical Status & Current Data

• Phase 2b Trial Results: In July 2025, data from a Phase 2b clinical trial showed that while inidascamine produced numerical improvements in memory and processing speed compared to a placebo, it failed to achieve statistical significance on its primary efficacy endpoint.
• Safety Profile: The drug demonstrated excellent tolerability. It lacked common antipsychotic side effects like heavy sedation, rapid weight gain, or involuntary body movements.
• Commercial Backing: Following the trial shortfall, atai Life Sciences officially deprioritized the asset to shift its primary funding toward its wholly owned pipeline of psychedelic therapies.

Inidascamine (INNTooltip International Nonproprietary Name; developmental code names RL-007, FSV7-007) is an experimental drug which is under development for the treatment of cognitive impairment associated with schizophrenia (CIAS).^{[1][3][4][5][6][2]} It is taken orally.^[1][2] The drug is said to act on the cholinergic, NMDA, and GABA_B receptor systems.^[1][5][2] Inidascamine is being developed by Recognify Life Sciences and atai Life Sciences.^[1][3] It was discovered via screening of compounds for effects on synaptic plasticity and cognition.^[2] The drug shows structural similarities to phenethylamines and amphetamines.^[7]

• A Study to Evaluate RL-007 in the Treatment of Cognitive Impairment Associated With Schizophrenia (CIAS)CTID: NCT05686239Phase: Phase 2Status: CompletedDate: 2025-07-30
• Safety, Biomarker Study of RL-007 in Subjects With SchizophreniaCTID: NCT04822883Phase: Phase 2Status: CompletedDate: 2022-04-27

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2006081273&_cid=P11-MQ616P-01336-1

OL-threo-2- Amino-3-hvdroxy-3 -(pyridin-4-yl)- 1 -(pyrrolidin- 1 -yDpropan- 1 -one dihydrochloride Compound 22.
Compound 22 was prepared following method E with trans-(4,5-άihydτo-5-(pyridin-4-yl)oxazol-4-yl)(pyrrolidin-l-yl)methanone Compound 19 (0.750 g, 3.07 mmol), hydrochloric acid 37 % (1.0 mL) and methanol (10 mL). After 3.0 h at 50 °C and work-up DL-tAreø-2-amino-3-hydroxy-3-(pyridin-4-yl)-l-(pyrrolidin-l-yl)propan-l-one dihydrochloride Compound 22 was obtained as a white solid (0.935 g, 99 % yield).

Compound 22
MW: 308.28; Yield: 99 %; White Solid; Mp (°C): 117.0.
¹H-NMR (CD₃OD₃ δ): 1.75-2.03 (m, 4H, 2xCH₂), 2.93-3.08 (m, 1H, CHN), 3.32-3.75 (m, 3H, 2xCH₂), 4.54 (d, 1H, J= 5.9 Hz, CH₁N), 5.40 (d, 1H, J = 5.9 Hz, CH-O), 8.21 (d, 2H, J= 5.8 Hz, ArH), 8.94 (d, 2H, J= 5.8 Hz, ArH).
MS-ESI m/z (% rel. int.): 236.1 ([MH]+, 17), 219 (25), 148 (100).
HPLC: Method A, detection UV 254 nm, Compound 22 RT = 0.8 min, peak area 96.3 %.

PAT

• 3-aryl-3-hydroxy-2-amino-propionic acid amides, 3-heteroaryl-3-hydroxy-2-amino-propionic acid amides and related compounds having analgesic and / or immunostimulatory activityPublication Number: ES-2565236-T3Priority Date: 2005-01-26Grant Date: 2016-04-01
• 3-ARYL-3-HYDROXY-2-AMINO-PROPIONIC ACID, 3-HETEROARYL-3-HYDROXY-2-AMINOPROPIONIC ACID AMIDES AND RELATED COMPOUNDS HAVING ANALGESIC AND/OR IMMUNOSTIMULATING ACTIVITYPublication Number: BR-122018068138-B1Priority Date: 2005-01-26
• 1-aryl-1-hydroxy-2,3-diamino-propyl amines, 1-heteroaryl-1-hydroxy-2,3-diamino-propyl amines and related compounds having analgesic and/or immuno stimulant activityPublication Number: US-2011288094-A1Priority Date: 2005-01-26
• 1-aryl-1-hydroxy-2,3-diamino-propyl amines, 1-heteroaryl-1-hydroxy-2,3-diamino-propyl amines and related compounds having analgesic and/or immuno stimulant activityPublication Number: US-9828349-B2Priority Date: 2005-01-26Grant Date: 2017-11-28
• Compounds having analgesic and/or immunostimulant activityPublication Number: US-2012157497-A1Priority Date: 2005-01-26
• 3-aryl-3-hydroxy-2-amino-propionic acid amides, 3-heteroaryl-3-hydroxy-2-amino-propionic acid amides and related compounds having analgesic and/or immunostimulant activityPublication Number: AU-2012241156-A1Priority Date: 2005-01-26
• 3-Aryl-3-hydroxy-2-amino-propionic acid amide, 3-heteroaryl-3-hydroxy-2-amino-propionic acid amide and related compounds having analgesic activity and / or immunostimulatory activityPublication Number: JP-2012162547-APriority Date: 2005-01-26

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Clinical data
Other names	RL-007; RL007; FSV7-007
Routes of administration	Oral[1][2]
Identifiers
IUPAC name
CAS Number	903884-71-9
PubChem CID	11535990
ChemSpider	9710771
UNII	3LW01V88B7
ChEMBL	ChEMBL5095258
CompTox Dashboard (EPA)	DTXSID90238113
Chemical and physical data
Formula	C12H17N3O2
Molar mass	235.287 g·mol−1
3D model (JSmol)	Interactive image
SMILES
InChI

References

1.  "RL 007". AdisInsight. 10 June 2024. Retrieved 26 February 2025.
2.  Donello JE, Walker GA, Schweighoffer F, and Pando MP. Abstract Number: 149. RL-007, a novel oral neuromodulator, enhances synaptic plasticity and cognition in non-clinical models. American College of Neuropsychopharmacology (ACNP) annual meeting. December 5, 2023. https://ir.atai.life/static-files/06c60339-e93c-42fc-9323-c0e38e83f86e
3.  "Delving into the Latest Updates on RL-007 with Synapse". Synapse. 23 January 2025. Retrieved 26 February 2025.
4.  Brady LS, Lisanby SH, Gordon JA (2023). "New directions in psychiatric drug development: promising therapeutics in the pipeline". Expert Opinion on Drug Discovery. 18 (8): 835–850. doi:10.1080/17460441.2023.2224555. PMID 37352473.
5.  Vita A, Barlati S, Cavallaro R, Mucci A, Riva MA, Rocca P, et al. (2024). "Definition, assessment and treatment of cognitive impairment associated with schizophrenia: expert opinion and practical recommendations". Frontiers in Psychiatry. 15 1451832. doi:10.3389/fpsyt.2024.1451832. PMC 11450451. PMID 39371908.
6.  Ye N, Wang Q, Li Y, Zhen X (March 2025). "Current emerging therapeutic targets and clinical investigational agents for schizophrenia: Challenges and opportunities". Medicinal Research Reviews. 45 (2): 755–787. doi:10.1002/med.22086. PMID 39300769.
7.  "2-Amino-3-hydroxy-3-(pyridin-4-yl)-1-(pyrrolidin-1-yl)propan-1-one, (2R,3S)-". PubChem. Retrieved 26 February 2025.

//////////inidascamine, ANAX LABS, schizophrenia, 3LW01V88B7, RL 007

#inidascamine, #ANAX LABS, #schizophrenia, #3LW01V88B7, #RL 007

Irodanoprost

 

Irodanoprost

CAS 2055490-48-5

MF C34H44F2N2O13P2 MW788.7 g/mol

7-[(2R)-2-[(E,3R)-4,4-difluoro-3-[2-[4-[(4-hydroxy-4,4-diphosphonobutyl)carbamoyl]phenyl]acetyl]oxy-4-phenylbut-1-enyl]-5-oxopyrrolidin-1-yl]heptanoic acid

(2R)-2-[(1E,3R)-4,4-Difluoro-3-[[2-[4-[[(4-hydroxy-4,4-diphosphonobutyl)amino]carbonyl]phenyl]acetyl]oxy]-4-phenyl-1-buten-1-yl]-5-oxo-1-pyrrolidineheptanoic acid

• 1-Pyrrolidineheptanoic acid, 2-[(1E,3R)-4,4-difluoro-3-[[2-[4-[[(4-hydroxy-4,4-diphosphonobutyl)amino]carbonyl]phenyl]acetyl]oxy]-4-phenyl-1-buten-1-yl]-5-oxo-, (2R)-
• 7-[(2R)-2-{(1E,3R)-4,4-difluoro-3-[({4-[(4-hydroxy-4,4-diphosphonobutyl)carbamoyl]phenyl}acetyl)oxy]-4-phenylbut-1-en-1-yl}-5-oxopyrrolidin-1-yl]heptanoic acid

7-[(2R)-2-{(1E,3R)-4,4-difluoro-3-[({4-[(4-hydroxy-4,4-diphosphonobutyl)carbamoyl]phenyl}acetyl)oxy]-4-phenylbut-1-en-1-yl}-5-oxopyrrolidin-1-yl]heptanoic acid
prostaglandin receptor agonist, osteogenesis-related diseases, KP8BK46Z6R, MES 1022

Irodanoprost (also known as MES-1022) is a clinical-stage, bone- and pathology-targeted small molecule prodrug that acts as a potent and selective agonist for the prostaglandin E2 receptor subtype 4 (EP4). Developed by the pharmaceutical company Mesentech Inc., the compound is designed to treat severe musculoskeletal and rare muscle-wasting diseases

Therapeutic Mechanism

Systemic activation of the EP4 receptor has long been known to stimulate bone and muscle regeneration. However, its clinical use was previously restricted due to toxic off-target side effects like severe hypotension and gastrointestinal issues.

Irodanoprost overcomes this barrier through a unique "pathology-targeted" conjugate design:

• Targeting Mechanism: The EP4 agonist is chemically linked to a moiety that binds selectively to calcium-rich tissues—such as bone matrices or damaged, dystrophic muscle fibers.
• Local Activation: Once it accumulates at the site of damage, it delivers localized therapeutic signaling while avoiding systemic tissues.

Primary Target Indications

The drug candidate is primarily under investigation for several rare or progressive degenerative diseases:

• Duchenne Muscular Dystrophy (DMD): Preclinical trials on advanced DMD rat models published in bioRxiv demonstrate that irodanoprost actively blocks the differentiation of fibro-adipogenic progenitors, effectively reversing established muscle fibrosis and restoring muscle mass to wild-type levels.
• Osteogenesis Imperfecta (Brittle Bone Disease): Utilizing its bone-anabolic pathway to promote bone growth and strength.
• Facioscapulohumeral Muscular Dystrophy (FSHD)
• Osteoporosis

PAT

EP-3307747-A1
US-10400000-B2
US-11312737-B2
US-20180170951-A1
US-20190345179-A1
WO-2016199111-A1

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016199111&_cid=P11-MQ7G6Y-06859-1

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PAT

• Amide-linked EP4 agonist-bisphosphonate compounds and uses thereofPublication Number: US-10400000-B2Priority Date: 2015-06-12Grant Date: 2019-09-03
• Amide-linked ep4 agonist-bisphosphonate compounds and uses thereofPublication Number: US-2019345179-A1Priority Date: 2015-06-12
• Amide-linked ep4 agonist-bisphosphonate compounds and uses thereofPublication Number: US-2018170951-A1Priority Date: 2015-06-12
• Amide-linked ep4 agonist-bisphosphonate compounds and uses thereofPublication Number: WO-2016199111-A1Priority Date: 2015-06-12
• Amide-linked ep4 agonist-bisphosphonate compounds and uses thereofPublication Number: EP-3307747-A1Priority Date: 2015-06-12
• Amide-linked EP4 agonist-bisphosphonate compounds and uses thereof
• Publication Number: US-11312737-B2
• Priority Date: 2015-06-12
• Grant Date: 2022-04-26

////////////irodanoprost, ANAX LABS, prostaglandin receptor agonist, osteogenesis-related diseases, KP8BK46Z6R, MES 1022

#irodanoprost, #ANAX LABS, #prostaglandin receptor agonist, #osteogenesis-related diseases, #KP8BK46Z6R, #MES 1022

Itareparib

 

Itareparib

CAS 1606995-47-4

MF C20H26FN3O2 MW359.4 g/mol

2-(1-Cyclohexyl-4-piperidinyl)-6-fluoro-2,3-dihydro-3-oxo-1H-isoindole-4-carboxamide

1H-ISOINDOLE-4-CARBOXAMIDE, 2-(1-CYCLOHEXYL-4-PIPERIDINYL)-6-FLUORO-2,3-DIHYDRO-3-OXO-

2-(1-cyclohexylpiperidin-4-yl)-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole4-carboxamide
poly (ADP-ribose) polymerase (PARP) inhibitor, antineoplastic, NMS-03305293, NMS-293, NMS 03305293, NMS 293, KFI1190L8L, NV 578,

Itareparib is the inhibitor for PARP and exhibits antineoplastic activity.

Itareparib (development code NMS-03305293 or NMS-293) is an experimental, next-generation PARP1-selective oral inhibitor being developed by the biopharmaceutical company Nerviano Medical Sciences for the treatment of various advanced solid tumors and brain cancers

Key Characteristics & Mechanism

Unlike first-generation poly(ADP-ribose) polymerase (PARP) inhibitors, itareparib features a highly specialized mechanism designed to improve clinical safety and versatility:

• Non-Trapping Profile: Traditional PARP inhibitors trap the PARP enzyme onto DNA, forming PARP-DNA complexes. This trapping causes significant bone marrow toxicity (myelosuppression), leading to severe side effects like anemia, neutropenia, and thrombocytopenia. Itareparib is engineered to be "non-trapping," avoiding these complexes to protect healthy blood cells.
• High Brain Penetrance: It crosses the blood-brain barrier effectively, making it uniquely suitable for treating primary and secondary central nervous system (CNS) malignancies.
• Ideal Combinability: Because it does not cause overlapping bone marrow toxicity, it can be safely paired with other DNA-damaging therapies like traditional chemotherapies and antibody-drug conjugates (ADCs).

Clinical Development & Target Indications

Itareparib is currently advancing through Phase I and Phase II clinical trials. It is being investigated across several oncology settings:

• Glioblastoma (GBM): Evaluated in Phase II clinical studies for relapsed, IDH wild-type glioblastoma in combination with the chemotherapy drug temozolomide (TMZ).
• Ovarian Cancer: Evaluated in Phase Ia/Ib trials (such as trial NCT06930755) in combination with topotecan for patients with recurrent, platinum-resistant ovarian, fallopian tube, or peritoneal cancers. [1]
• Small Cell Lung Cancer (SCLC) & Astrocytoma: Explored in ongoing combination trials targeting highly aggressive tumors where conventional PARP inhibitors are limited by overlapping toxicity.

• Study of NMS-03305293 in Adult Patients With Relapsed Ovarian CancerCTID: NCT06930755Phase: Phase 1Status: RecruitingDate: 2026-05-28
• Study of NMS-03305293 in Adult Patient With Relapsed Small Cell Lung CancerCTID: NCT06931626Phase: Phase 1Status: RecruitingDate: 2025-11-12
• Ph I/II Study of NMS-03305293+TMZ in Adult Patients With Recurrent GlioblastomaCTID: NCT04910022Phase: Phase 1/Phase 2Status: Active, not recruitingDate: 2025-08-19
• Study of NMS-03305293 in Pts with Selected Advanced/Metastatic Solid TumorsCTID: NCT04182516Phase: Phase 1Status: TerminatedDate: 2024-09-19

A Phase I/II Combination Study of NMS-03305293 and Temozolomide in Adult Patients with Recurrent Glioblastoma

EudraCT: 2020-003417-35

Phase: Phase 1, Phase 2

Status: Trial now transitioned

Date: 2021-11-10

SYN

US10800739,

https://patentscope.wipo.int/search/en/detail.jsf?docId=US275481284&_cid=P10-MQA9O8-42416-1

2-(1-Cyclohexyl-piperidin-4-yl)-6-fluoro-3-oz-2,3-dihydro-1H-isoindole-4-carboxylic Acid Amide (I), cpd 29 [R═F; n=m=0; R1=piperidin-4-yl; R2=1-cyclohexyl]

To a stirred solution of 2-(1-cyclohexyl-piperidin-4-yl)-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carbonitrile (IV) (100 mg, 0.3 mmol) in acetic acid (5 mL), concentrated sulfuric acid (2.7 mL) was added dropwise during 30 min. The reaction was then warmed at 80° C. for 9 h, cooled at room temperature and poured into cold water (10 mL). The aqueous phase was then made basic by adding concentrated aqueous ammonia and extracted with dichloromethane (3×10 mL). The combined organic phases were washed with 2N aqueous sodium hydroxide (2×12 mL) and brine, dried over Na 2SO 4 and evaporated to dryness in vacuo. The title compound was obtained as a white solid (43 mg, 40%) after purification through column chromatography ((dichloromethane/methanol/ammonia solution, 7N in methanol:97/2/1).

1H NMR (400.5 MHz, DMSO-d 6) δ ppm 1.00-1.14 (m, 1H), 1.14-1.28 (m, 4H), 1.53-1.61 (m, 1H), 1.67-1.80 (m, 6H), 2.25-2.36 (m, 3H), 2.88-2.95 (m, 2H), 3.94-4.03 (m, 1H), 4.55 (s, 2H), 7.66 (dd, J HF=7.7, J HH=2.6 Hz, 1H), 7.85 (br. s., 1H), 7.89 (dd, J HF=10.9, J HH=2.6 Hz, 1H), 10.78 (br. s., 1H).

HRMS (ESI+): calcd. for C 20H 27FN 32 [M+H] + 3602082: found 360.2098.

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014064149&_cid=P10-MQA9K8-39764-1

2-(1-Cyclohexyl-piperidin-4-yl)-6-fluoro-3-oxo-2,3-dihydro-1 H-isoindole-4-carboxylic acid amide (I), cpd 29

[R = F; n = m = 0; R1 = piperidin-4-yl; R2 = 1-cyclohexyl]

To a stirred solution of 2-(1-cyclohexyl-piperidin-4-yl)-6-fluoro-3-oxo-2,3-dihydro-1 H-isoindole-4-carbonitrile (IV) (100 mg, 0.3 mmol) in acetic acid (5 mL), concentrated sulfuric acid (2.7 mL) was added dropwise during 30 min. The reaction was then warmed at 80 °C for 9 h, cooled at room temperature and poured into cold water (10 mL). The aqueous phase was then made basic by adding concentrated aqueous ammonia and extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with 2N aqueous sodium hydroxide (2 X 12 mL) and brine, dried over Na2S04 and evaporated to dryness in vacuo. The title compound was obtained as a white solid (43 mg, 40%) after purification through column chromatography ((dichloromethane/methanol/ammonia solution, 7N in methanol: 97/2/1).

¹H NMR (400.5 MHz, DMSO- cfe) δ ppm 1.00 - 1.14 (m, 1 H), 1.14 - 1.28 (m, 4 H), 1.53 - 1.61 (m, 1 H), 1.67 - 1.80 (m, 6 H), 2.25 - 2.36 (m, 3 H), 2.88 - 2.95 (m, 2 H), 3.94 - 4.03 (m, 1 H), 4.55 (s, 2 H), 7.66 (dd, JHF = 7.7, JHH = 2.6 Hz, 1 H), 7.85 (br. s., 1 H), 7.89 (dd, JHF = 10.9, JHH = 2.6 Hz, 1 H), 10.78 (br. s., 1 H).

HRMS (ESI+): calcd. for C20H27FN3O2 [M + H]⁺ 360.2082; found 360.2098

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• 4-carboxamido-isoindolinone derivatives as selective parp-1 inhibitorsPublication Number: US-2020407314-A1Priority Date: 2012-10-26
• 4-carboxamido-isoindolinone derivatives as selective PARP-1 inhibitorsPublication Number: US-11773064-B2Priority Date: 2012-10-26Grant Date: 2023-10-03
• 4-Carboxamide-isoindolinone derivatives as selective PARP-1 inhibitorsPublication Number: JP-6314147-B2Priority Date: 2012-10-26Grant Date: 2018-04-18
• 4-carboxamido-isoindolinone derivatives as selective PARP-1 inhibitorsPublication Number: ES-2813530-T3Priority Date: 2012-10-26Grant Date: 2021-03-24
• 4-carboxamido-isoindolinone derivatives as selective PARP-1 inhibitorsPublication Number: US-10385018-B2Priority Date: 2012-10-26Grant Date: 2019-08-20
• 4-carboxamido-isoindolinone derivatives as selective parp-1 inhibitorsPublication Number: US-2015274662-A1Priority Date: 2012-10-26
• 4-carboxamido-isoindolinone derivatives as selective parp-1 inhibitorsPublication Number: WO-2014064149-A1Priority Date: 2012-10-26
• 4-carboxamido-isoindolinone derivatives as selective parp-1 inhibitorsPublication Number: US-11420940-B2Priority Date: 2012-10-26Grant Date: 2022-08-23
• DERIVATIVES OF 4-CARBOXAMIDO-ISOINDOLINONA AS SELECTIVE INHIBITORS OF PARP-1.Publication Number: MX-2015005245-APriority Date: 2012-10-26
• 4-carboxamido-isoindolinone derivatives as selective parp-1 inhibitorsPublication Number: US-2019330151-A1Priority Date: 2012-10-26
• COMPOUNDS DERIVED FROM 4-CARBOXAMIDO-ISOINDOLINONE, PROCESS OF PREPARATION OF THESE, IN VITRO METHOD TO SELECTIVELY INHIBIT PARP-1 PROTEIN ACTIVITY, PHARMACEUTICAL COMPOSITION AND USE OF THE REFERRED COMPOUNDSPublication Number: BR-112015009130-B1Priority Date: 2012-10-26
• 4-carboxamido-isoindolinone derivatives as selective parp-1 inhibitorsPublication Number: US-2022363636-A1Priority Date: 2012-10-26
• 4-carboxamido-isoindolinone derivatives as selective parp-1 inhibitorsPublication Number: CA-2889581-A1Priority Date: 2012-10-26
• 4-carboxamido-isoindolinone derivatives as selective PARP-1 inhibitorsPublication Number: US-10800739-B2Priority Date: 2012-10-26Grant Date: 2020-10-13
• 4-carboxamido-isoindolinone derivatives as selective parp-1 inhibitorsPublication Number: EP-2912032-A1Priority Date: 2012-10-26
• 4-carboxamido-isoindolinone derivatives as selective parp-1 inhibitorsPublication Number: EP-2912032-B1Priority Date: 2012-10-26Grant Date: 2020-05-27
• DERIVATIVES 4-CARBOXAMIDO-ISOINDOLINONE AS PARP-1 SELECTIVE INHIBITORS, METHOD FOR THEIR PRODUCTION AND APPLICATIONPublication Number: EA-028506-B1Priority Date: 2012-10-26
• 4-Formylamino-isoindolinone derivatives as selective PARP-1 inhibitorsPublication Number: CN-104768948-APriority Date: 2012-10-26
• 4-carboxamido-isoindolinone derivatives as selective parp-1 inhibitorsPublication Number: CA-2889581-CPriority Date: 2012-10-26Grant Date: 2021-06-29

////////itareparib, ANAX LABS, poly (ADP-ribose) polymerase (PARP) inhibitor, antineoplastic, NMS-03305293, NMS-293, NMS 03305293, NMS 293, KFI1190L8L, NV 578,

#itareparib, #ANAX LABS, #poly (ADP-ribose) polymerase (PARP) inhibitor, #antineoplastic, #NMS-03305293, #NMS-293, #NMS 03305293, #NMS 293, #KFI1190L8L, #NV 578,