Thursday, 1 October 2026

Nivegacetor

 

Nivegacetor

CAS 2443487-67-8

MF C23H25F2N7O2 MW 469.5 g/mol

(R)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine and (S)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine

(7R)-7-(3,5-difluorophenoxy)-N-[(1S,5R)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine

(7R)-7-(3,5-difluorophenoxy)-N-[(1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine
gamma secretase modulator, SF4J7MVJ56, RG 6289, RG-6289, ROCHE, ALZHIEMER,

Nivegacetor is a potent γ-secretase modulator.

Nivegacetor is an investigational gamma-secretase modulator being developed by Roche for the treatment of Alzheimer's disease.[1] The compound is also known by its development code name RG6289 and represents a second-generation gamma-secretase modulator designed to selectively alter amyloid beta peptide production while avoiding the toxicity issues associated with first-generation compounds.[2]

Mechanism of action

Nivegacetor is a gamma-secretase modulator (GSM) that targets the gamma-secretase enzyme complex, which plays a central role in the production of amyloid beta peptides implicated in the pathogenesis of Alzheimer's disease.[1] It specifically modulates the catalytic subunit presenilin-1 (PSEN1), stabilizing the interaction between the complex and the amyloid precursor protein (APP) at the enzyme's active site. This stabilization increases the processivity of APP cleavage—that is, the enzyme's ability to carry out sequential cleavage steps before releasing the APP substrate.[3]

Unlike gamma-secretase inhibitors that completely block enzyme function and cause significant side effects, nivegacetor selectively reduces the production of amyloidogenic long amyloid beta peptides, particularly Aβ42 and Aβ40 that form insoluble amyloid fibrils, while simultaneously increasing the formation of shorter, non-amyloidogenic species such as Aβ38 and Aβ37. The compound demonstrates high potency with an IC50 below 10 nM for gamma-secretase modulation of APP cleavage, and importantly shows no effect on the processing of other gamma-secretase substrates, potentially avoiding the toxicity issues that plagued earlier compounds.[2]

A Study of Donanemab, RG6289, or the Combination of Donanemab and RG6289 in Presenilin 1 (PSEN1) E280A Mutation Carriers for the Treatment of Autosomal-Dominant Alzheimer's Disease

CTID: NCT06996730

Phase: Phase 2/Phase 3

Status: Not yet recruiting

Date: 2025-08-03

  • OriginatorRoche
  • ClassAntidementias; Azabicyclo compounds; Bridged bicyclo compounds; Ethers; Fluorobenzenes; Methyl ethers; Pyridazines; Pyrrolidines; Triazoles
  • Mechanism of ActionAmyloid precursor protein secretase modulator
  • Phase IIAlzheimer's disease
  • 03 Dec 2025Efficacy data from a phase II trial in Alzheimer's disease presented at the Alzheimer's Association International Conference 2025 (AAIC-2025)
  • 13 Aug 2025Chemical structure information added.
  • 14 Nov 2024Banner Alzheimers Institute and Neurosciences Group at the University of Antioquia (GNA) in Medellin plans a clinical trial for Alzheimer's-disease (Monotherapy, Prevention, In adults), in fall 2025 (IV) (NCT06996730)

SYN

US12195470,

https://patentscope.wipo.int/search/en/detail.jsf?docId=US351843428&_cid=P22-MLYKGQ-06478-1

xamples 1 and 2

(R)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine and (S)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine

A Buchwald type coupling using the general procedure 1, between 2-bromo-7-(3,5-difluorophenoxy)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole 7-1 and (1R,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-2, followed by a separation of the enantiomeres by preparative chiral HPLC afforded the title products as white solid (example 1): 27 mg, MS (ES+) m/z: 470.2 [(M+H) +] and (example 2): 28 mg, MS (ES+) m/z: 470.2 [(M+H) +].

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020120521&_cid=P22-MLYK91-02083-1

Examples 1 and 2

(R)-7-(3,5-difluorophenoxy)-N-((lR,5S,8s)-3-(6-methoxypyridazin-4-yl)-3- azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-amine

and

(S)-7-(3,5-difluorophenoxy)-N-((lR,5S,8s)-3-(6-methoxypyridazin-4-yl)-3- azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-amine

A Buchwald type coupling using the general procedure 1, between 2-bromo-7-(3,5-difluorophenoxy)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole 7-1 and (lR,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine 8-2, followed by a separation of the enantiomeres by preparative chiral HPLC afforded the title products as white solid (example 1): 27 mg, MS (ES+) m/z 470.2 [(M+H)+] and (example 2): 28 mg, MS (ES+) m/z 470.2 [(M+H)+]

PAT

str1

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Clinical development

Phase I studies

Nivegacetor has completed Phase I clinical trials in healthy volunteers, where it demonstrated a favorable safety profile and dose-dependent pharmacodynamic effects.[3] The study showed that treatment with nivegacetor resulted in a dose-dependent shift in amyloid beta monomers in cerebrospinal fluid (CSF), with significant reductions in Aβ42 levels and corresponding increases in shorter amyloid beta species.[4]

The Phase I results were presented at the 2023 Clinical Trials on Alzheimer's Disease (CTAD) conference, where researchers reported that nivegacetor appeared safe and effectively shifted amyloid beta production toward smaller, less aggregation-prone peptides.[3]

Phase II studies

Based on the positive Phase I results, nivegacetor has been selected for advancement to Phase II clinical trials for Alzheimer's disease treatment.[3] The dose selection for the Phase II study was informed by population pharmacokinetic/pharmacodynamic modeling derived from the Phase I data.[5][6][7]

Historical context

Nivegacetor represents a significant advancement in gamma-secretase modulator development, addressing the limitations of first-generation compounds that failed due to toxicology problems.[2] Previous attempts at gamma-secretase modulation were hampered by safety concerns and off-target effects, leading to the discontinuation of several promising candidates in the 2000s and early 2010s.[2] The development of nivegacetor as a second-generation GSM reflects improved understanding of gamma-secretase biology and more selective targeting approaches.[8]

References

  1.  "nivegacetor | Ligand page". IUPHAR/BPS Guide to IMMUNOPHARMACOLOGY. International Union of Basic and Clinical Pharmacology (IUPHAR). Retrieved 22 July 2025.
  2.  "RG6289". ALZFORUM. Archived from the original on 9 October 2024. Retrieved 22 July 2025.
  3.  "Second-Generation γ-Secretase Modulator Heads to Phase 2". ALZFORUM. Retrieved 22 July 2025.
  4.  "Y-Secretase Modulator RG6289 Produces Dose-Dependent Shift of Amyloid-ß Monomers in Phase 1 Study". Neurology live. 30 July 2024. Retrieved 22 July 2025.
  5.  "RG6289, a new γ-secretase modulator for the treatment of Alzheimer's disease: Dose selection for a phase II trial based on population PK/PD modeling". medically.gene.com. Retrieved 22 July 2025.
  6.  Banner Health (21 May 2025). A Double-Blind, Placebo-Controlled, Double-Dummy Study of Donanemab and RG6289 in PSEN1 E280A Mutation Carriers, and in Non-Randomized, Placebo-Treated Non-Carriers From the Same Kindred, to Evaluate the Efficacy and Safety of Donanemab, RG6289, or the Combination of Donanemab and RG6289, in the Treatment of Autosomal-Dominant Alzheimer's Disease (Report). clinicaltrials.gov. NCT06996730.
  7.  azalzeditor (19 November 2024). "New Alzheimer's prevention trial receives $74.5 million NIH grant". Arizona Alzheimer's Consortium. Retrieved 22 July 2025.
  8.  Nordvall G, Lundkvist J, Sandin J (16 October 2023). "Gamma-secretase modulators: a promising route for the treatment of Alzheimer's disease". Frontiers in Molecular Neuroscience. 16 1279740. doi:10.3389/fnmol.2023.1279740. ISSN 1662-5099. PMC 10613654. PMID 37908487.
Identifiers
IUPAC name
CAS Number2443487-67-8
PubChem CID153606610
IUPHAR/BPS13509
UNIISF4J7MVJ56
KEGGD13199
Chemical and physical data
FormulaC23H25F2N7O2
Molar mass469.497 g·mol−1
3D model (JSmol)Interactive image
SMILES
InChI

/////////nivegacetor, gamma secretase modulator, SF4J7MVJ56, RG 6289, RG-6289, ROCHE, ALZHIEMER,

#nivegacetor, #gamma secretase modulator, #SF4J7MVJ56, #RG 6289, #RG-6289, #ROCHE, #ALZHIEMER,

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Ocadusertib

 

Ocadusertib

CAS 2382811-41-6

MF C25H25N5O4 MW 459.5 g/mol

5-benzyl-N-[(3S)-7-(3-hydroxy-3-methylbut-1-ynyl)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1H-1,2,4-triazole-3-carboxamide

5-benzyl-N-[(3S)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]-1H-1,2,4-triazole-3-carboxamide
serine/threonine kinase inhibitor, LY3871801, R552, LY 3871801, R 552, S53J4A7ME4

  • OriginatorRigel Pharmaceuticals
  • DeveloperEli Lilly and Company; Rigel Pharmaceuticals
  • ClassAnti-inflammatories; Antirheumatics; Small molecules
  • Mechanism of ActionRIPK1 protein inhibitors
  • Phase IIRheumatoid arthritis
  • No development reportedUnspecified
  • 28 Mar 2025No recent reports of development identified for phase-I development in Unspecified(In volunteers) in Singapore (PO, Suspension)
  • 14 Nov 2024Pharmacodynamics data from preclinical trials in Rheumatoid arthritis presented at the ACR Convergence 2024 (ACR-2024)
  • 14 Nov 2024Safety and pharmacokinetics data from a phase I trial in Rheumatoid arthritis presented at the ACR Convergence 2024 (ACR-2024)

Ocadusertib (LY3871801/R552) is an oral, potent, and selective small-molecule RIPK1 inhibitor developed by Rigel Pharmaceuticals and Eli Lilly for autoimmune and inflammatory diseases. It is currently in Phase 2 clinical trials for treating moderate-to-severe rheumatoid arthritis. ACR Meeting AbstractsACR Meeting Abstracts +4

Key Aspects of Ocadusertib:

  • Mechanism of Action: It inhibits receptor-interacting serine/threonine-protein kinase 1 (RIPK1), which blocks necroptotic (cell death) responses and, consequently, reduces inflammation.
  • Target Indications: Primarily focused on rheumatoid arthritis, it has also been investigated for psoriasis and general inflammatory joint conditions.
  • Development Status: As of late 2025, it is in Phase 2 clinical trials (NCT05848258), with previous trials evaluating its safety, tolerability, and pharmacokinetics in healthy volunteers.
  • Characteristics: It is designed to be a selective inhibitor, showing no significant inhibition in a broad panel of other kinases. ACR Meeting AbstractsACR Meeting Abstracts +3

Ocadusertib is a small molecule drug. The usage of the INN stem '-sertib' in the name indicates that Ocadusertib is a serine/threonine kinase inhibitor. Ocadusertib is under investigation in clinical trial NCT05848258 (An Adaptive Phase 2a/2b Study of LY3871801 in Adult Participants With Rheumatoid Arthritis). Ocadusertib has a monoisotopic molecular weight of 459.19 Da.

  • An Adaptive Phase 2a/2b Study of LY3871801 in Adult Participants With Rheumatoid ArthritisCTID: NCT05848258Phase: Phase 2Status: RecruitingDate: 2025-12-09
  • A Study of LY3871801 in Healthy Asian and Non-Asian ParticipantsCTID: NCT05960851Phase: Phase 1Status: CompletedDate: 2024-01-10
  • A Drug Interaction Study of LY3871801 in Healthy ParticipantsCTID: NCT05602675Phase: Phase 1Status: CompletedDate: 2023-04-18
  • A Study of LY3871801 in Healthy ParticipantsCTID: NCT05222399Phase: Phase 1Status: CompletedDate: 2022-03-18

SYN

PAT

PAT

WO 2014/125444

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014125444&_cid=P20-MM02QM-54301-1

PAT

I-30: (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide (WO 2014/125444), having a structure as illustrated below, was used as a comparative compound and was examined using a similar protocol as described by WO 2014/125444. This comparison

compound exhibited 93% inhibition at a dose of 30 mg/kg according to WO 2014/125444; however, in the inventors hands, the compound inhibited only 70% at 30 mg/kg. In comparison, compound I-30 of the present disclosure achieved greater than 85% inhibition at a dose of just 5 mg/kg using the similar assay protocol described above.

PAT

str1

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///////ocadusertib, serine/threonine kinase inhibitor, LY3871801, R552, LY 3871801, R 552, S53J4A7ME4

#ocadusertib, #serine/threonine kinase inhibitor, #LY3871801, #R552, #LY 3871801, #R 552, #S53J4A7ME4

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Olomorasib

 

Olomorasib

CAS 2771246-13-8

MF C25H19ClF2N4O3S MW528.96

4-[(13aS)-10-chloro-8-fluoro-6-oxo-2-prop-2-enoyl-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazocin-9-yl]-2-amino-7-fluoro-1-benzothiophene-3-carbonitrile

Benzo[b]thiophene-3-carbonitrile, 2-amino-4-[(4aS)-8-chloro-10-fluoro-2,3,4,4a,5,6-hexahydro-12-oxo-3-(1-oxo-2-propen-1-yl)-1H,12H-pyrazino[2,1-d][1,5]benzoxazocin-9-yl]-7-fluoro-, (4R)-

(4M)-2-amino-4-[(4aS)-8-chloro-10-fluoro-12-oxo-3-(prop-2-enoyl)-2,3,4,4a,5,6-hexahydro-1H,12H-pyrazino[2,1-d][1,5]benzoxazocin-9-yl]-7-fluoro-1-benzothiophene-3-carbonitrile
Kirsten rat sarcoma viral oncogene homolog (KRAS) inhibitor, antineoplastic, LY3537982, LY 3537982, KRAS-G12C-II, LY-3537982, C2VJ83PSN7,

Olomorasib (LY3537982) is an investigational, oral, second-generation KRAS G12C inhibitor designed to treat advanced solid tumors, particularly non-small cell lung cancer (NSCLC). Developed by Eli Lilly and Company, it shows promising antitumor activity and a manageable safety profile, often combined with pembrolizumab (Keytruda). Eli Lilly and CompanyEli Lilly and Company +3

Key details about olomorasib include:

  • Mechanism & Target: It targets the KRAS G12C mutation, a common driver in lung and colorectal cancers.
  • Clinical Status: It is undergoing Phase 1/2 (LOXO-RAS-20001) and Phase 3 (SUNRAY-01) clinical trials.
  • Breakthrough Therapy: The FDA granted Breakthrough Therapy designation for first-line treatment of advanced NSCLC (PD-L1  50%) in September 2025.
  • Combination Efficacy: When combined with pembrolizumab, it showed an objective response rate of 73.9% in first-line patients, with higher efficacy in those with high PD-L1 expression.
  • Safety Profile: Common adverse events include diarrhea, elevated liver enzymes (ALT/AST), and rash, which were generally manageable. Eli Lilly and CompanyEli Lilly and Company +4

Olomorasib is designed to be more potent with potentially better tolerability than earlier KRAS G12C inhibitors, aiming to improve outcomes in first-line settings.

  • OriginatorEli Lilly and Company
  • ClassAntineoplastics; Small molecules
  • Mechanism of ActionKRAS protein inhibitors
  • Phase IIINon-small cell lung cancer
  • Phase ISolid tumours
  • 05 Jan 2026Eli Lilly and Company completes a phase-I trial (In volunteers) in Japan (PO, Capsule) (NCT07124013)
  • 22 Dec 2025Phase-I/II clinical trials in Non-small cell lung cancer (Metastatic disease, Second-line therapy or greater, Combination therapy) in USA, Canada, China, South Korea (PO) (NCT07227025)
  • 12 Nov 2025Janssen Research & Development plans a phase I/II (KaRAnaSa) trial for Non-small cell lung cancer (Combination Therapy, Metastatic disease, Second-line therapy or greater) in December 2025 (NCT07227025)

Olomorasib is an orally available inhibitor of the oncogenic KRAS substitution mutation, G12C, with potential antineoplastic activity. Upon oral administration, olomorasib selectively targets the KRAS G12C mutant and inhibits KRAS G12C mutant-dependent signaling. KRAS, a member of the RAS family of oncogenes, serves an important role in cell signaling, division and differentiation. Mutations of KRAS may induce constitutive signal transduction leading to tumor cell growth, proliferation, invasion, and metastasis.

Olomorasib (LY3537982) is an experimental anticancer drug which acts as an inhibitor of the G12C mutant form of Kirsten rat sarcoma virus (KRAS), an oncogene commonly present in several forms of cancer. It is in early stage clinical trials against lung and colorectal cancers and advanced solid tumors.[1][2][3][4][5]

PAPER

ACS Omega. 2025 Jul 4;10(27):29637-29646. [Abstract]

PATENT
•Patent. US20240307395A1.

PAPER

https://www.nature.com/articles/s41598-025-07532-2

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021118877&_cid=P10-MM1FNU-88391-1

Example 34

4-[( 13 aS)- 10-Chloro-8-fluoro-6-oxo-2-prop-2-enoyl- 1,3,4,12, 13,13 a- hexahydropyrazino[2,ld][1,5]benzoxazocin-9-yl]-2-amino-benzothiophene-3- carbonitrile

A suspension of 4-[(13aS)-10-chloro-8-fluoro-6-oxo-2,3,4,12,13,13a-hexahydro-lH-pyrazino[2,ld][l,5]benzoxazocin-9-yl]-2-amino-benzothiophene-3-carbonitrile (1.58 g, 3.46 mmol) in EtOAc (35 mL), THF (15 mL) and water (40 mL) is charged with potassium carbonate (1.90 g, 13.7 mmol). The mixture is stirred rapidly and cooled to 0 °C. Acryloyl chloride in DCM (13.0 mL, 3.25 mmol, 0.25M) is added dropwise through a dropping funnel. After 10 minutes of stirring in an ice bath, the mixture is diluted with EtOAc and poured into a separatory funnel. The layers are separated and the aqueous layer is again extracted with EtOAc. The combined organic extracts are washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue is purified by silica gel flash column chromatography, eluting first with 0-100% (10% MeOH in DCM) / DCM, and second with 0-100% [10% (7N NH 3 in MeOH) in DCM] / DCM to give the desired product as fluffy solid. The solid is sonicated in ether for 30 minutes, filtered, and dried in high vacuum to give the title compound (1.60 g, 91%). ES/MS m/z ( 35 C1/ 37 C1) 511.0/513.0 [M+H] + .

Table 22: Compounds synthesized in a manner essentially analogous to that of Example

PAT

str1

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References

  1.  Peng SB, Si C, Zhang Y, Van Horn RD, Lin X, Gong X, et al. (July 2021). "Preclinical characterization of LY3537982, a novel, highly selective and potent KRAS-G12C inhibitor". Cancer Research. 81 (13_Supplement): 1259. doi:10.1158/1538-7445.AM2021-1259.
  2.  Miyashita H, Hong DS (2024). "Combining EGFR and KRAS G12C Inhibitors for KRAS G12C Mutated Advanced Colorectal Cancer". Journal of Cancer Immunology. 6 (2): 62–69. doi:10.33696/cancerimmunol.6.086. PMC 11340593. PMID 39175850.
  3.  Hollebecque A, Kuboki Y, Murciano-Goroff YR, Yaeger R, Cassier PA, Heist RS, et al. (2024). "Efficacy and safety of LY3537982, a potent and highly selective KRAS G12C inhibitor in KRAS G12C-mutant GI cancers: Results from a phase 1 study". Journal of Clinical Oncology. 42 (3_suppl): 94. doi:10.1200/JCO.2024.42.3_suppl.94.
  4.  Burns TF, Dragnev KH, Fujiwara Y, Murciano-Goroff YR, Lee DH, Hollebecque A, et al. (2024). "Efficacy and safety of olomorasib (LY3537982), a second-generation KRAS G12C inhibitor (G12Ci), in combination with pembrolizumab in patients with KRAS G12C-mutant advanced NSCLC". Journal of Clinical Oncology. 42 (16_suppl): 8510. doi:10.1200/JCO.2024.42.16_suppl.8510.
  5.  Heist RS, Koyama T, Murciano-Goroff YR, Hollebecque A, Cassier PA, Han J, et al. (2024). "Pan-tumor activity of olomorasib (LY3537982), a second-generation KRAS G12C inhibitor (G12Ci), in patients with KRAS G12C-mutant advanced solid tumors". Journal of Clinical Oncology. 42 (16_suppl): 3007. doi:10.1200/JCO.2024.42.16_suppl.3007.
Clinical data
Other namesLY3537982
Identifiers
IUPAC name
CAS Number2649788-46-3
PubChem CID156472638
ChemSpider115009373
UNIIC2VJ83PSN7
KEGGD12853
Chemical and physical data
FormulaC25H19ClF2N4O3S
Molar mass528.96 g·mol−1
3D model (JSmol)Interactive image
SMILES
InChI

///////olomorasib, Kirsten rat sarcoma viral oncogene homolog (KRAS) inhibitor, antineoplastic, LY3537982, LY 3537982, KRAS-G12C-II, LY-3537982, C2VJ83PSN7,

#olomorasib, #Kirsten rat sarcoma viral oncogene homolog (KRAS) inhibitor, #antineoplastic, #LY3537982, #LY 3537982, #KRAS-G12C-II, #LY-3537982, #C2VJ83PSN7,

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Wednesday, 30 September 2026

Milsaperidone

 

Milsaperidone

CAS 501373-88-2

C24H29FN2O4 MW 428.50

FDA APPROVED 2/20/2026, Bysanti, To treat schizophrenia and to treat manic or mixed episodes associated with bipolar I disorder

(1S)-1-[4-[3-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]propoxy]-3-methoxyphenyl]ethanol

7SV1ZOG031, P-88-8991, (-)-, (S)-Hydroxy Iloperidone, P-88, VHX 869, VHX-896

Milsaperidone (INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name), also known by its developmental code name VHX-896 and its tentative brand name Bysanti, is an atypical antipsychotic which is pending approval for the treatment of schizophrenia and bipolar disorder and is in phase 3 clinical trials for treatment of major depressive disorder.[1][2][3] It is a prodrug of iloperidone (Fanapt) and acts as a dopamine D2 receptor and serotonin 5-HT2A receptor antagonist, among other actions.[1][4][5] The drug was developed by Vanda Pharmaceuticals.[1]

  • OriginatorVanda Pharmaceuticals
  • Class2 ring heterocyclic compounds; Alcohols; Anisoles; Antidepressants; Antipsychotics; Ethers; Fluorobenzenes; Isoxazoles; Methyl ethers; Mood stabilisers; Phenyl ethers; Piperidones; Small molecules
  • Mechanism of ActionAlpha 1 adrenergic receptor antagonists; Dopamine D2 receptor antagonists; Serotonin 5-HT2 receptor antagonists
  • RegisteredBipolar disorders; Schizophrenia
  • 25 Feb 2026Chemical structure information added.
  • 25 Feb 2026Vanda Pharmaceuticals has patent protection for an improved method of treatment with milsaperidone in USA
  • 25 Feb 2026Vanda Pharmaceuticals has patents pending for an improved method of treatment with milsaperidone in China, Australia, Israel, Mexico and worldwide

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2003020707&_cid=P20-MM2TQZ-44406-1

Example 1

(S)-1-(4-(3-r4-(6-Fluoro-benzofd1isoxazol-3-vπ-piperidin-1-vπ-propoxy)-3-methoxy-phenvπ-ethanol

56.36 g of boran complex of (3aR, 7R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1 ,3,2]oxazaborole (1 equivalent) is dissolved under nitrogen in methylenchloride, and the solution is cooled to 0°C. A 1M solution of 1-(4-{3-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-propoxy}-3-methoxy-phenyl)-ethanone (iloperidone; 1 equivalent) in methylenchloride is added via a dropping funnel over 90 minutes while the internal temperature is maintained at 0°C ± 2°C. After the addition is complete, the mixture is stirred at 0°C for 20 hours. The reaction mixture is then poured into precooled methanol (0-5°C) during 1 hour. The solution is warmed to room temperature and stirred until the H2 evolution ceases. The solution is concentrated by distillation and the residue dried in vacuum, treated with methanol and stirred for about 1 hour at 50°C and an additional hour at 0CC. The product is isolated by filtration and dried under reduced pressure for 3 hours at 50°C. The title compound is obtained (white crystals).

[α]D20- 19.3° (c=1 in chloroform)
Mp: 138.2 - 138.8°C

The boran complex used as starting material can be obtained as follows:

200 ml of a solution of (3aR, 7R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole (1M in toluene) is stirred at room temperature under nitrogen. 1.2 equivalent borane-dimethylsulfide complex is added with a syringe. The solution is stirred for 2 further hours at room temperature. The borane complex is then crystallised by addition of 4 vol dry hexane and cooling to -12°C for 1.5 hour. The product is isolated by filtration in a sintered glass funnel and dried in vacuum at 40°C. The boran complex is obtained /white crystals).

Example 2

(R)-1-(4-(3-r4-(6-Fluoro-benzord1isoxazol-3-vπ-piperidin-1-vn-propoxy)-3-methoxy-phenlvπ-ethanol

This compound is produced in analogy to Example 1, using boran complex of (3aS, 7R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole.

[α]D20 = + 18.4° (c=1 in chloroform)
Mp: 137.9 - 138.3°C

PAT

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References

  1.  "Vanda Pharmaceuticals". AdisInsight. 30 July 2025. Retrieved 11 October 2025.
  2.  IsHak WW, Hirsch D, Renteria S, Totlani J, Murphy N, Chang T, et al. (October 2025). "Depressive disorders: systematic review of approved psychiatric medications (2009-April 2025) and pipeline phase 3 medications". BMC Psychiatry. 25 (1) 939. doi:10.1186/s12888-025-07141-3. PMC 12506068. PMID 41057811.
  3.  Richmond LM (1 June 2025). "Med Check: FDA Accepts Bysanti Application, Cobenfy Fails as Adjunct, and More". Psychiatric News. 60 (6) appi.pn.2025.06.6.2. doi:10.1176/appi.pn.2025.06.6.2. ISSN 0033-2704. Retrieved 11 October 2025.
  4.  Kang J (9 May 2025). "Milsaperidone Under Review for Bipolar I Disorder and Schizophrenia". MPR. Retrieved 11 October 2025.
  5.  "Vanda Announces Bysanti™ NDA Filing; FDA Decision Expected in Early 2026". BioSpace. 5 May 2025. Retrieved 11 October 2025.
Clinical data
Trade namesBysanti
Other namesVHX896
Routes of
administration		Oral
Drug classAtypical antipsychotic
Identifiers
IUPAC name
CAS Number501373-88-2
PubChem CID10365268
ChemSpider8540717
UNII7SV1ZOG031
KEGGD13099
Chemical and physical data
FormulaC24H29FN2O4
Molar mass428.504 g·mol−1
3D model (JSmol)Interactive image
SMILES
InChI

////////////milsaperidone, FDA 2026, APPROVALS 2026, Bysanti, schizophrenia, 7SV1ZOG031, P-88-8991, (-)-, (S)-Hydroxy Iloperidone, P-88, VHX 869, VHX-896

#milsaperidone, #FDA 2026, #APPROVALS 2026, #Bysanti, #schizophrenia, #7SV1ZOG031, #P-88-8991, #(-)-, (S)-Hydroxy Iloperidone, #P-88, #VHX 869, #VHX-896

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