Ceperognastat

Ceperognastat

CAS 2241514-56-5

MF C16H22FN5O3S MW383.4 g/mol

Acetamide, N-(4-fluoro-5-(((2S,4S)-2-methyl-4-((5-methyl-1,2,4-oxadiazol-3-yl)methoxy)-1-piperidinyl)methyl)-2-thiazolyl)-

N-[4-fluoro-5-({(2S,4S)-2-methyl-4-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]piperidin-1-yl}methyl)-1,3-thiazol-2-yl]acetamide
O-GlcNAcase (OGA) enzyme inhibitor, LY3372689, LY3372689, U0SGP6ZX2V

Ceperognastat (LY3372689) is a drug candidate molecule under investigation to treat Alzheimer’s disease. It targets the enzyme O-GlcNAcase.^[2][3] Its result is to reduce formation of tau protein tangles.

A molecule containing radioactive fluorine was used with a PET scan to show that ceperognastat binds in the human brain.^[4]

Ceperognastat was discovered via a high-throughput screening campaign followed by further optimization.^[5]

Eli Lilly and Company is recruiting subjects for a clinical trial.^[6] Some hospitals in Australia: St Vincent’s Hospital, Sydney Hornsby Ku-Ring-Gai Hospital, The Prince Charles Hospital, The Queen Elizabeth Hospital, Adelaide, Box Hill Hospital, and Delmont Private Hospital are involved.^[7] Results of the trial were expected by June 2024.^[8] Primary completion of the study occurred on 9th July 2024, with full completion expected in August 2024. In an investor call, it was disclosed that ceperognastat missed the primary endpoint of improvement on the Integrated Alzheimer’s Disease Rating Scale. The detailed results of this study are expected to be disclosed at a conference in late 2024.^[9]

Chemical

The molecule contains three rings: thiazole, piperidine and oxadiazole. Other functional groups included are an ether, acetamide, and a fluoride.^[10]

• A Study of LY3372689 to Assess the Safety, Tolerability, and Efficacy in Participants With Alzheimer’s DiseaseCTID: NCT05063539Phase: Phase 2Status: CompletedDate: 2025-07-28
• A Study of the Effects of Multiple Doses of LY3372689 on the Brain in Healthy ParticipantsCTID: NCT04392271Phase: Phase 1Status: CompletedDate: 2020-11-04
• A Safety Study of LY3372689 in Healthy ParticipantsCTID: NCT04106206Phase: Phase 1Status: CompletedDate: 2020-04-24
• A Study of the Effects of LY3372689 on the Brain in Healthy ParticipantsCTID: NCT03944031Phase: Phase 1Status: CompletedDate: 2020-04-22
• A Safety Study of LY3372689 Given By Mouth to Healthy ParticipantsCTID: NCT03819270Phase: Phase 1Status: CompletedDate: 2019-07-05

REF

• Discovery and clinical translation of ceperognastat, an O‐GlcNAcase (OGA) inhibitor, for the treatment of Alzheimer’s diseasePublication Name: Alzheimer’s & Dementia: Translational Research & Clinical InterventionsPublication Date: 2024-10PMCID: PMC11694536PMID: 39748851DOI: 10.1002/trc2.70020
• Discovery of 4-(Arylethynyl)piperidine Derivatives as Potent Nonsaccharide O-GlcNAcase Inhibitors for the Treatment of Alzheimer’s DiseasePublication Name: Journal of Medicinal ChemistryPublication Date: 2024-08-07PMID: 39109492DOI: 10.1021/acs.jmedchem.4c01132

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=US224106869&_cid=P22-MO2ADF-16767-1

EXAMPLE 1

Synthesis of N-[4-fluoro-5-[[(2S,5S)-2-methyl-4-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]-1-piperidyl]methyl]thiazol-2-yl]acetamide

N-(4-Fluoro-5-formyl-thiazol-2-yl)acetamide (28.3 g, 150 mmol) is added to 5-methyl-3-[[(2S,4S)-2-methyl-4-piperidyl]oxymethyl]-1,2,4-oxadiazole hydrochloride (48.7 g, 185 mmol, 94% purity) in ethyl acetate (707 mL) at room temperature. The reaction mixture is stirred at room temperature and N,N-diisopropylethylamine (34.1 mL, 195 mmol) is added dropwise over 1 minute, then sodium triacetoxyborohydride (98.5 g, 451 mmol) is added in one portion. The reaction mixture is stirred in a 31° C. heating block overnight with an internal temperature of 30° C., then is cooled in an ice-water bath to an internal temperature of 5° C. To the mixture is added 2M aqueous hydrochloric acid solution (226 mL) over 15 minutes, maintaining an internal temperature below 10° C. To the mixture is added water (250 mL) and the mixture is stirred at room temperature for 5 minutes. The layers are separated and the organic layer is extracted with a mixture of 2M aqueous hydrochloric acid solution (28 mL) in water (50 mL). The first aqueous layer is stirred in an ice-water bath and 50% aqueous sodium hydroxide solution (25.7 mL) is added dropwise over 10 minutes, maintaining an internal temperature below 10° C. The mixture is diluted with saturated aqueous sodium bicarbonate solution (100 mL), then is stirred at room temperature for 10 minutes and then is extracted with ethyl acetate (3×400 mL). The combined organics are dried over sodium sulfate, filtered and concentrated to give a residue. The second aqueous layer from the extraction with aqueous hydrochloric acid is diluted with 2-methyltetrahydrofuran (200 mL) and the mixture is passed through a short pad of diatomaceous earth. The filtrate is transferred to a separating funnel and the layers are separated. The aqueous layer is stirred in an ice-water bath and 50% aqueous sodium hydroxide solution (3.15 mL) is added dropwise over 5 minutes, maintaining an internal temperature below 10° C. The mixture is diluted with saturated aqueous sodium bicarbonate solution (10 mL), then is stirred at room temperature for 5 minutes and then is extracted with ethyl acetate (3×40 mL) and 10% isopropanol in ethyl acetate (100 mL). The combined organics are dried over sodium sulfate, filtered and concentrated to give a residue, which is combined with the residue from the first part of the workup. The combined residue is passed through a pad of silica gel (350 g) eluting with ethyl acetate (3.5 L) and the filtrate is concentrated to give a residue (45.8 g).

The residue (47.5 g of combined lots, 123.9 mmol) is purified by flash chromatography, eluting with 50-100% ethyl acetate in heptane. The product-containing fractions are concentrated to residue, which is suspended in a 1:1 mixture of methyl-tert-butyl ether and heptane (448 mL). The mixture is stirred in a 46° C. heating block for 30 minutes at an internal temperature of 45° C., then is cooled to room temperature over 2 hours with stirring. The mixture is filtered, washing the solid with a 1:1 mixture of methyl-tert-butyl ether and heptane (30 mL). The filtered solid is dried under vacuum at 40° C. overnight to give the title compound (28.5 g). MS m/z 384.0 (M+H); [α] D 20=+33.4° (C=0.26, methanol).

PAT

• N-[4-fluoro-5-[[(2s,4s)-2-methyl-4-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]-1-piperidyl]methyl]thiazol-2-yl]acetamide as oga inhibitorPublication Number: EP-3573983-B1Priority Date: 2017-01-27Grant Date: 2021-04-21
• N-[4-fluoro-5-[[(2s,4s)-2-methyl-4-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]-1-piperidyl]methyl]thiazol-2-yl]acetamide as oga inhibitorPublication Number: NZ-754849-APriority Date: 2017-01-27
• N- [4-Fluoro-5-[[(2S, 4S) -2-methyl-4-[(5-methyl-1,2,4-oxadiazol-3-yl) methoxy] as OGA inhibitor -1-piperidyl] methyl] thiazol-2-yl] acetamidePublication Number: JP-2020504142-APriority Date: 2017-01-27
• N-[4-fluoro-5-[[(2S,4S)-2-methyl-4-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]-1-piperidyl]methyl] Thiazol-2-yl]acetamide as an inhibitor of OGAPublication Number: IL-267693-APriority Date: 2017-01-27
• Acetamide N-[4-fluor-5-]](4S,2S)-2-methyl-4-](5-methyl-1,2,4-oxadiazole-3-yl)methoxy[-1-piperdyl[methyl] [Thiazole-2-yl] as an OGA inhibitorPublication Number: JO-P20190182-A1Priority Date: 2017-01-27
• N-[4-FLUORO-5-[[(2S,4S)-2-METHYL-4-[(5-METHYL-1,2,4-OXADIAZOLE-3-IL)METHOXI]-1-PIPERIDIL]METHYL]THIAZOLE-2-IL] ACETAMIDE AS AN OGA INHIBITOR.Publication Number: MX-387166-BPriority Date: 2017-01-27
• N-[4-fluoro-5-[[(2s,4s)-2-methyl-4-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]-1-piperidyl]methyl]thiazol-2-yl]acetamide as oga inhibitorPublication Number: MY-197494-APriority Date: 2017-01-27

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References

References

1.  “Data Sheet LY3372689” (PDF). 26 December 2024. Retrieved 4 February 2025.
2.  “LY3372689”. www.alzforum.org.
3.  Cheng, Steven S.; Mody, Alison C.; Woo, Christina M. (2024-11-07). “Opportunities for Therapeutic Modulation of O-GlcNAc”. Chemical Reviews. 124 (22): 12918–13019. doi:10.1021/acs.chemrev.4c00417. ISSN 0009-2665. PMID 39509538.
4.  Shcherbinin, Sergey; Kielbasa, William; Dubois, Susan; Lowe, Stephen L; Phipps, Krista M; Tseng, James; Kevin, Donnelly B; Natanegara, Fanni; Warner, Susan; Dreyfus, Nicolas; Lindsay-Scott, Peter; Hawk, Mai Khanh; McDonald, Nicholas; Zhang, Xiaoyu; Gilmore, Julie A; Biglan, Kevin; Mergott, Dustin J; Russell, David; Gunn, Roger N; Constantinescu, Cristian; Nuthall, Hugh Norman; Collins, Emily C (December 2020). “Brain target occupancy of LY3372689, an inhibitor of the O-GlcNAcase (OGA) enzyme: Translation from rat to human: Neuroimaging / evaluating treatments”. Alzheimer’s & Dementia. 16 (S4). doi:10.1002/alz.040558. S2CID 227501893.
5.  Kielbasa, William; Goldsmith, Paul; Donnelly, Kevin B.; Nuthall, Hugh N.; Shcherbinin, Sergey; Fleisher, Adam S.; Hendle, Jörg; DuBois, Susan L.; Lowe, Stephen L.; Zhang, Feiyu Fred; Woerly, Eric M.; Dreyfus, Nicolas J.-F.; Evans, David; Gilmore, Jeremy; Mancini, Michele (October 2024). “Discovery and clinical translation of ceperognastat, an O-GlcNAcase (OGA) inhibitor, for the treatment of Alzheimer’s disease”. Alzheimer’s & Dementia: Translational Research & Clinical Interventions. 10 (4) e70020. doi:10.1002/trc2.70020. ISSN 2352-8737. PMC 11694536. PMID 39748851.
6.  “Assessment of Safety, Tolerability, and Efficacy of LY3372689 in Early Symptomatic Alzheimer’s Disease”. clinicaltrials.gov. 22 March 2022. Retrieved 31 March 2022.
7.  “A Study of LY3372689 to Assess the Safety, Tolerability, and Efficacy in Participants With Alzheimer’s Disease”. Retrieved 31 March 2022.
8.  Krietsch Boerner, Leigh (25 March 2022). “Hybrid meeting divulges structures of drug candidates”. Chemical & Engineering News. ISSN 0009-2347.
9.  edge.media-server.com https://edge.media-server.com/mmc/p/3kqnwjy6/. Retrieved 2024-10-06. {{cite web}}: Missing or empty |title= (help)
10.  Dreyfus, Nicolas Jacques Francois; Lindsay-Scott, Peter James (2 August 2018). “N-[4-Fluoro-5-[[(2S,4S)-2-Methyl-4-[(5-Methyl-1,2,4-Oxadiazol-3-Yl)methoxy]-1-Piperidyl]methyl]thiazol-2-Yl]acetamide as Oga Inhibitor”. Retrieved 31 March 2022.

Names
IUPAC nameN-[4-fluoro-5-[[2-methyl-4-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]piperidin-1-yl]methyl]-1,3-thiazol-2-yl]acetamide
Identifiers
CAS Number	2241514-56-5 [1]
3D model (JSmol)	Interactive image
ChemSpider	129432852
PubChem CID	135271363
InChI
SMILES
Properties
Chemical formula	C16H22FN5O3S
Molar mass	383.44 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).Infobox references

/////////ceperognastat, O-GlcNAcase (OGA) enzyme inhibitor, LY3372689, LY3372689, U0SGP6ZX2V