Thursday, 1 October 2026

Nispomeben

 

Nispomeben

CAS 1443133-41-2

MF C21H27NO4 MW357.4 g/mol

N-[(2S)-1-(4-hydroxyphenyl)-3-[(2S)-2-hydroxypropoxy]propan-2-yl]-3-phenylpropanamide

N-{(2S)-1-(4-hydroxyphenyl)-3-[(2S)-2-hydroxypropoxy]propan-2-yl}-3-phenylpropanamide
non-opioid analgesic, 470338M5XD,  E1, NRD 135S E1, NRD E1, NRD.E1, NRD135S, NRD135S.E1, NRD135SE.1

Nispomeben is a small molecule drug. Nispomeben has a monoisotopic molecular weight of 357.19 Da.

  • OriginatorNovaremed
  • ClassAlcohols; Amides; Anti-inflammatories; Benzene derivatives; Non-opioid analgesics; Phenols; Small molecules
  • Mechanism of ActionLyn protein-tyrosine kinase modulators
  • Phase IINeuropathic pain
  • 02 Sep 2025Updated adverse events data from a phase II trial in Neuropathic pain released by Novaremed
  • 07 May 2025Novaremed completes enrolment in a phase-II clinical trial in Neuropathic pain in USA (PO) (NCT05480228)
  • 16 Sep 2022Phase-II clinical trials in Neuropathic pain in USA (PO) (NCT05480228)

PAT

WO 2013/084238

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013084238&_cid=P12-MLVQKQ-84446-1

The present invention is based in part on the surprising discovery that the substantially pure enantiomers (S)2-N(3-0-((S)propan 2-ol)-l-propyl-4-hydroxybenzene)-3-phenylpropylamide (also known as the (S,S) enantiomer or El) and (S)2-N(3-0-((R)propan 2-ol)-l -propyl -4-hydroxybenzene)-3-phenylpropyl amide (also known as the (S,R) enantiomer or E2) modulate the activity of specific tyrosine kinases in an opposite manner. It was unexpectedly found that while the (S,S) enantiomer activated protein tyrosine kinases LynA and BLK, the (S,R) enantiomer inhibited their activity. It was further unexpectedly shown that the (S,S) enantiomer was effective as a pain analgesic in animal models of pain, while the (S,R) enantiomer was shown to be ineffective or less effective in these models. Furthermore, the analgesic effect of the (S,S) enantiomer was long acting as it was efficacious for more than 24 hours post administration, in comparison to the commonly used analgesic agent gabapentin which was effective for no longer than 5 hours post administration.

The isolated enantiomers according to some embodiments of the invention may be synthesized as a racemate by known in the art methods described for example in US 7,754,771, US 7,642,290, US 7,674,829 or US 2011/0086910. The racemate may be further separated by known in the art methods for the separation of chiral compounds. According to an exemplary embodiment, the enantiomers may be synthesized as a racemate (comprising (S)2-N(3-0-((S)propan 2-ol)-l-propyl-4-hydroxybenzene)-3-phenylpropylamide and (S)2-N(3-0-((R)propan 2-ol)-l-propyl-4-hydroxybenzene)-3-phenylpropylamide and be further separated by a supercritical fluid chromatography (SFC) in combination with chiral stationary phases. Specifically, the (S,S) and (S,R) compounds may be separated on RegisPack™ column a polysaccharide coated chiral column (with a tris-(3,5-dimethylphenyl) carbamoyl cellulose selector) generally used for enantiomeric separations of a wide range of racemate classes (Figure 7A-C).

According to some embodiments, the enantiomers may be synthesized directly using for example, the process described in scheme 1 for the preparation of the (S,S) enantiomer.

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US73212948&_cid=P12-MLVQ44-77600-1

The bis-protected ether (15.7 g) was exposed to one-pot hydrogenation-debenzylation conditions (10% loading of 10% Pd/C and 0.25 eq of p-toluenesulfonic acid) in methanol. After 2 hours at 60° C. under a hydrogen atmosphere, HPLC analysis indicated that the hydrogenation of the benzyl and the debenzylation of PMB ring was complete. The reaction mixture was filtered over Celite and concentrated under reduced pressure. The residue was dissolve in ethyl acetate and a saturated aqueous sodium bicarbonate treatment was conducted to effectively remove p-toluenesulfonic acid, then DURP to provide 12.13 g of an oil (PR030-120-4). Desired product was isolated from an EA/Heptane recrystallization to provide 8.83 g of a white solid (PR030-120-6, 89.4% yield). The purity of PR030-120-6 was 99.3% via HPLC analysis. 1H NMR and Mass spec analysis supported the assigned structure for desired product.

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020152226&_cid=P12-MLVQFW-82529-1

((S,S)-2-N(3-0-(propan-2-ol)-1 -propyl-4-hydroxybenzene)-3-phenylpropylamide), including its enantiomers and diastereomers may be prepared as described in WO 2013/084238,

Example 1 - Preparation of -2-N(3-Q-(propan-2-ol)-1-propyl-4-hvdroxybenzene)-3- 

phenylpropylamide

(S,S)-2-N(3-0-(propan-2-ol)-1 -propyl-4-hydroxybenzene)-3-phenylpropylamide was prepared as described in WO 2013/084238 and US 201 1/0086910.

In a first step, 2 g of methyl lactate was reacted with excess of benzyl bromide to get 880 mg of (S)-benzyloxymethyl lactate. The reaction was performed by slurring sodium hydride in THF and cooling down to approximately -15°C. The reaction mixture was then allowed to warm slowly to room temperature and stirred for approximately 1 to 2 hours. The reaction was quenched with saturated ammonium chloride solution and extracted with MTBE twice followed by the removal of solvent on a rotary evaporator to obtain a crude oil. The crude product was purified by column chromatography to yield pure (S)-2-benzyloxymethyl lactate. The (R)-2-benzyloxymethyl lactate isomer was present at 0.93% only. The yield of this step may be increased by avoiding the presence of moisture in the reaction solution.

In a second step, 880 mg (S)-2-benzyloxymethyl lactate obtained in step 1 were reduced using lithium aluminum hydride to obtain (S)-2-benzyloxypropylene glycol in 83.8% yield with 98.7% purity. A solution of pure (S)-2-benzyloxymethyl lactate in methylene chloride was stirred and a solution of lithium aluminum hydride was slowly added thereto at approximately 5°C. The reaction was monitored by TLC and quenched by USP-PW water very carefully. No racemization occurred in this step.

In a third step, the (S)-2-benzyloxypropylene glycol was then reacted with methane sulfonyl chloride in methylene chloride in the presence of triethyl amine to yield the mesylate in 88% yield. A solution of step 2 was stirred in methylene chloride and methane sulfonyl chloride was added to it dropwise at <5°C. After the addition was complete, the progress of the reaction was monitored by TLC. The reaction was quenched with USP-PW water. After the layers were separated, the aqueous layer was back extracted with methylene chloride. The methylene chloride layers were then combined and washed with USP-PW water 3 times to remove most of the methane sulfonic acid. No racemization occurred in this step.

In a fourth step, the mesylate (of step 3) was coupled with S-O-benzyl tyrosinol to form the bis-protected product in 22.7% yield, with a purity of 97.4%. The reaction was carried out at room temperature using a combination of DMF as the solvent and sodium hydride as the base. The reaction went to completion after stirring for at least 12 hours at room temperature.

In a fifth step, 340 mg of the product of step 4 were reduced by hydrogenation in the presence of 10% palladium on carbon catalyst and hydrochloric acid using methylene chloride as a solvent at 50°C. The reaction went to completion in approximately 4 hours with no racemization to yield the desired product in 84.3% yield and 98.9% purity. More specifically, the catalyst was removed by filtration and the filtrate was then concentrated at 33°C. The resulting mixture of solid and oil was mixed with ethyl acetate. The resulting slurry was filtered and the solids washed with ethyl acetate and dried under vacuum at 40 to 45°C to obtain the desired product.

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US346680873&_cid=P12-MLVQFW-82529-1

Example 1—Preparation of (S,S)-2-N(3-O-(propan-2-ol)-1-propyl-4-hydroxybenzene)-3-phenylpropylamide

      (S,S)-2-N(3-O-(propan-2-ol)-1-propyl-4-hydroxybenzene)-3-phenylpropylamide was prepared as described in WO 2013/084238 and US 2011/0086910.
      In a first step, 2 g of methyl lactate was reacted with excess of benzyl bromide to get 880 mg of (S)-benzyloxymethyl lactate. The reaction was performed by slurring sodium hydride in THF and cooling down to approximately −15° C. The reaction mixture was then allowed to warm slowly to room temperature and stirred for approximately 1 to 2 hours. The reaction was quenched with saturated ammonium chloride solution and extracted with MTBE twice followed by the removal of solvent on a rotary evaporator to obtain a crude oil. The crude product was purified by column chromatography to yield pure (S)-2-benzyloxymethyl lactate. The (R)-2-benzyloxymethyl lactate isomer was present at 0.93% only. The yield of this step may be increased by avoiding the presence of moisture in the reaction solution.
      In a second step, 880 mg (S)-2-benzyloxymethyl lactate obtained in step 1 were reduced using lithium aluminum hydride to obtain (S)-2-benzyloxypropylene glycol in 83.8% yield with 98.7% purity. A solution of pure (S)-2-benzyloxymethyl lactate in methylene chloride was stirred and a solution of lithium aluminum hydride was slowly added thereto at approximately 5° C. The reaction was monitored by TLC and quenched by USP-PW water very carefully. No racemization occurred in this step.
      In a third step, the (S)-2-benzyloxypropylene glycol was then reacted with methane sulfonyl chloride in methylene chloride in the presence of triethyl amine to yield the mesylate in 88% yield. A solution of step 2 was stirred in methylene chloride and methane sulfonyl chloride was added to it dropwise at <5° C. After the addition was complete, the progress of the reaction was monitored by TLC. The reaction was quenched with USP-PW water. After the layers were separated, the aqueous layer was back extracted with methylene chloride. The methylene chloride layers were then combined and washed with USP-PW water 3 times to remove most of the methane sulfonic acid. No racemization occurred in this step.
      In a fourth step, the mesylate (of step 3) was coupled with S—O-benzyl tyrosinol to form the bis-protected product in 22.7% yield, with a purity of 97.4%. The reaction was carried out at room temperature using a combination of DMF as the solvent and sodium hydride as the base. The reaction went to completion after stirring for at least 12 hours at room temperature.
      In a fifth step, 340 mg of the product of step 4 were reduced by hydrogenation in the presence of 10% palladium on carbon catalyst and hydrochloric acid using methylene chloride as a solvent at 50° C. The reaction went to completion in approximately 4 hours with no racemization to yield the desired product in 84.3% yield and 98.9% purity. More specifically, the catalyst was removed by filtration and the filtrate was then concentrated at 33° C. The resulting mixture of solid and oil was mixed with ethyl acetate. The resulting slurry was filtered and the solids washed with ethyl acetate and dried under vacuum at 40 to 45° C. to obtain the desired product.

PAT

str1

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////////nispomeben, non-opioid analgesic, 470338M5XD,  E1, NRD 135S E1, NRD E1, NRD.E1, NRD135S, NRD135S.E1, NRD135SE.1, Neuropathic pain

#nispomeben, #non-opioid analgesic, #470338M5XD, #E1, #NRD 135S E1, #NRD E1, #NRD.E1, #NRD135S, #NRD135S.E1, #NRD135SE.1, #Neuropathic pain

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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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