Zanvipixant

CAS 2166558-11-6

MF C17H12F5N7O MW 425.3 g/mol

[(6S)-1-(5-fluoropyrimidin-2-yl)-6-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridin-5-yl]-[3-fluoro-2-(trifluoromethyl)-4-pyridinyl]methanone

METHANONE, ((6S)-1-(5-FLUORO-2-PYRIMIDINYL)-1,4,6,7-TETRAHYDRO-6-METHYL-5H-1,2,3-TRIAZOLO(4,5-C)PYRIDIN-5-YL)(3-FLUORO-2-(TRIFLUOROMETHYL)-4-PYRIDINYL)-

[(6S)-1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl][3-fluoro-2-
(trifluoromethyl)pyridin-4-yl]methanone
purinoreceptor (P2X) antagonist, JNJ-55308942, JNJ 55308942, B7YN3CQ7S7,

JNJ-55308942 is under investigation in clinical trial NCT05328297 (A Study of JNJ-55308942 in the Treatment of Bipolar Depression).

JNJ-55308942 is an investigational drug that works as a P2X7 antagonist with a downstream effect of reducing interleukin-1β release.^[1][2][3] It is developed by Janssen Pharmaceuticals for bipolar depression.^[4]

Zanvipixant (JNJ-55308942) is an investigational small-molecule, brain-penetrant, and potent antagonist of the P2X7 receptor developed by Janssen (J&J). It is primarily studied for its potential to treat neuroinflammation-related conditions, including mood disorders and depression, by inhibiting P2X7-mediated IL-1β release. 

Key Details for Zanvipixant:

• Target: P2X7 Receptor (P2X7R).
• Mechanism: Brain-penetrant antagonist reducing neuroinflammation, specifically inhibiting microglial IL-1β release.
• Chemical Properties: Structure typically includes a triazolopyridine moiety.
• Development Status: Evaluated as a potential CNS treatment for conditions related to neuroinflammation, with research highlighting its pharmacological profile, including good CNS partitioning.
• Alternative Name: JNJ-55308942.

Research indicates that the P2X7 receptor is activated by high levels of extracellular ATP during stress, leading to inflammation and behavioral deficits associated with depression. Zanvipixant has been studied in this context as a potential therapeutic intervention.

• A Study of JNJ-55308942 in the Treatment of Bipolar DepressionCTID: NCT05328297Phase: Phase 2Status: CompletedDate: 2025-07-11
• A Study in Healthy Participants to Evaluate the Effects of Multiple Doses of JNJ-55308942 on Cytochrome P450 Substrate Activity and on the Pharmacokinetics of Levonorgestrel/Ethinyl EstradiolCTID: NCT03547024Phase: Phase 1Status: CompletedDate: 2025-04-27
• A Positron Emission Tomography (PET) Study to Investigate P2X7 Receptor Occupancy by JNJ-55308942 Using [18F]-JNJ-64413739CTID: NCT03437590Phase: Phase 1Status: CompletedDate: 2025-04-27
• A Study to Investigate the Safety, Tolerability, and Pharmacokinetics of JNJ-55308942 in Healthy Male and Female ParticipantsCTID: NCT03151486Phase: Phase 1Status: CompletedDate: 2025-04-27
• A Randomized, Stratified, Double-blind, Placebo-Controlled Study to Investigate the Efficacy, Safety and Tolerability of JNJ-55308942 in Bipolar Depression
• EudraCT: 2021-004790-31
• Phase: Phase 2
• Status: Ongoing, Completed
• Date: 2022-05-31

SYN

A Dipolar Cycloaddition Reaction To Access 6-Methyl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridines Enables the Discovery Synthesis and Preclinical Profiling of a P2X7 Antagonist Clinical Candidate

Publication Name: Journal of Medicinal Chemistry

Publication Date: 2017-12-20

PMID: 29211470

DOI: 10.1021/acs.jmedchem.7b01279

SYN

US9464084,

https://patentscope.wipo.int/search/en/detail.jsf?docId=US152971783&_cid=P20-MN4071-78379-1

Example 228

(S*)-(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)(1-(5-fluoropyrimidin-2-yl)-6-methyl-6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridin-5(4H)-yl)methanone

MS (ESI) mass calcd C ₁₇H ₁₂F ₅N ₇O, 425.1 m/z. found, 426.1 [M+H] ⁺.

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014152604&_cid=P20-MN3ZS0-66502-1

Example 228 (S)-(3 -fluoro-2-(trifluoromethyl)pyridin-4-yl)( 1 -(5 -fluoropyrimidin-2-yl)-6-methyl-6J-dihvdro-lH-ri,2,31triazolor4,5-c1pyridin-5(4H)-yl)methanone

he title compound was prepared as described in Example 65, substituting (S)-l-(5-fluoropyrimidin-2-yl)-6-methyl-4,5,6,7-tetrahydro-lH-[l,2,3]triazolo[4,5-c]pyridine-hydrochloride salt (prepared as Step 2 intermediate of method II synthesis) in Example 220 for l-pyrimidin-2-yl-4,5,6,7-tetrahydro-lH-[l,2,3]triazolo[4,5-c]pyridine, 3-fluoro-2-(trifluoromethyl)isonicotinic acid for 2-chloro-3-(trifluoromethyl)benzoic acid and Hunig’s base (3.0 equiv) for Et₃N. The powder x-ray diffraction pattern for this compound is shown in Figure 2. Alternatively, the title compound was synthesized using the following procedure:

Step 1 : (S)-l-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)-2-methylpiperidin-4-one

(S)-l-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)-2-methylpiperidin-4-one.: (S)-2-methylpiperidin-4-one, TFA salt (108 g, 478 mmol, 1.0 equiv.) was suspended in DCM (1.4 L). Et₃ (265 mL, 1.9 mol, 4.0 equiv.) and 3-fluoro-2-(trifluoromethyl)isonicotinoyl

chloride (1 19 g, 526 mmol, 1.1 equiv.) were added sequentially. The reaction solution was stirred at room temperature for 1 h. The precipitated solid was filtered and washed with EtOAc. The filtrate solution was concentrated and the residue was re-dissolved in EtOAc (500 mL). The organic layer was washed with saturated aHC03 aqueous solution, water and brine, dried over Na₂S0₄, and concentrated. The crude product was triturated from EtOAc/hexanes to afford (S)-l-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)-2-methylpiperidin-4-one (103 g, 368 mmol, 77%), which was used without further purification. MS = 305.1 (positive mode)

Step 2: (S)-(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)(l-(5-fluoropyrimidin-2-yl)-6-methyl-6,7-dihvdro-lH-ri ,2,31triazolor4,5-c1pyridin-5(4H)-yl)methanone and (S)-(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)(l-(5-fluoropyrimidin-2-yl)-4-methyl-6J-dihydro-lH

[ 1.2.3 Itriazolo [4.5 -c]pyridin-5 (4H)-yl)methanone

In a 5 L, three-neck, round-bottom flask equipped with a mechanic stirring, Dean-Stark trap, reflux condenser and an internal thermometer, to the solution of (S)-l-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)-2-methylpiperidin-4-one, prepared in Step 1 above (100 g, 328 mmol, 1.0 equiv.) in toluene (1.5 L), -toluenesulphonic acid (0.62 g, 3.29 mmol, 0.01 equiv.), pyrrolidine (33 mL, 394 mmol, 1.2 equiv.) and 2-azido-5-fluoropyrimidine (59.4 g, 427 mmol, 1.3 equiv.) were added sequentially. The reaction mixture was heated to reflux temperature for 4 hours and then cooled to room temperature. aHC03 (55.2 g, 657 mmol, 2.0 equiv.) and mCPBA (162 g, 657 mmol, 2.0 equiv.) solution in EtOAC (-250 mL) were added sequentially. After stirring at room temperature for 2 hours, water and EtOAc were added. The organic layer was washed sequentially with 1M a₂S0₃, saturated aHC0₃ aqueous solution, and brine, dried over Na₂S0₄, and concentrated. The crude product was purified via column chromatography to afford a mixture of (S)-(3-fluoro-2-

(trifluoromethyl)pyridin-4-yl)(l-(5-flu^

[l,2,3]triazolo[4,5-c]pyridin-5(4H)-yl)methanone and (S)-(3-fluoro-2- (trifluoromethyl)pyridin-4-yl)(l-(5-fl^^

[l,2,3]triazolo[4,5-c]pyridin-5(4H)-yl)methanone in a 10: 1 ratio (97 grams).

Step 3 : (S)-(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)(l -(5-fluoropyrimidin-2-yl)-6-methyl-6.7-dihvdro-lH-ri.2.31triazolor4.5-c1pyridin-5(4H)-yl)methanone

HPLC purification of the mixture from Step 2 was performed via achiral SFC (Stationary phase: Chiralcel OD-H 5μιη 250x30mm), (Mobile phase: 75% C0₂, 25% MeOH) to afford pure (S)-(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)(l-(5-fluoropyrimidin-2-yl)-6-methyl-6,7-dihydro-lH-[l,2,3]triazolo[4,5-c]pyridin-5(4H)-yl)methanone (73 gram, 172 mmol, 52%). MS (ESI) mass calcd Ci₇H₁₂F_{5 7}0, 425.1 m/z found, 426.1 [M+H]⁺. ^XH NMR (500 MHz, CDC1₃) δ 8.84 – 8.69 (m, 2H), 8.68 – 8.57 (m, 1H), 7.71 – 7.49 (m, 1H), 5.90 -5.68 (d, J = 16.4 Hz, 0.5H), 5.66 – 5.54 (m, 0.5H), 4.76 – 4.58 (d, J = 15.8 Hz, 0.5H), 4.58 – 4.48 (m, 0.5H), 4.45 – 4.33 (m, 0.5H), 4.20 – 4.09 (m, 0.5H), 3.56 – 3.12 (m, 2H), 1.48 -1.18 (m, 3H).

2-chloro-3-(trifluoromethyl)benzoic acid and Hunig’s base (3.0 equiv) for Et₃N. MS (ESI) mass calcd Ci₇H₁₂F₅ 70, 425.1 m/z found, 426.1 [M+H]⁺.

PAT

• P2X7 modulatorsPublication Number: US-9464084-B2Priority Date: 2013-03-14Grant Date: 2016-10-11
• P2X7 MODULATORSPublication Number: PT-2970267-TPriority Date: 2013-03-14
• P2X7 modulatorsPublication Number: US-11225478-B2Priority Date: 2013-03-14Grant Date: 2022-01-18
• P2X7 modulatorPublication Number: JP-6293861-B2Priority Date: 2013-03-14Grant Date: 2018-03-14
• P2X7 modulatorsPublication Number: AU-2019203186-A1Priority Date: 2013-03-14
• P2X7 modulatorsPublication Number: TW-201446762-APriority Date: 2013-03-14
• P2X7 regulatorsPublication Number: CN-110003200-APriority Date: 2013-03-14
• P2X7 modulatorsPublication Number: US-9066946-B2Priority Date: 2013-03-14Grant Date: 2015-06-30

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References

 “CTG Labs – NCBI”. clinicaltrials.gov. Retrieved 27 November 2023.

 Bhattacharya, Anindya; Lord, Brian; Grigoleit, Jan-Sebastian; He, Yingbo; Fraser, Ian; Campbell, Shannon N.; Taylor, Natalie; Aluisio, Leah; O’Connor, Jason C.; Papp, Mariusz; Chrovian, Christa; Carruthers, Nicholas; Lovenberg, Timothy W.; Letavic, Michael A. (December 2018). “Neuropsychopharmacology of JNJ-55308942: evaluation of a clinical candidate targeting P2X7 ion channels in animal models of neuroinflammation and anhedonia”. Neuropsychopharmacology. 43 (13): 2586–2596. doi:10.1038/s41386-018-0141-6. ISSN 0893-133X. PMC 6224414. PMID 30026598.

 Bhattacharya, Anindya; Ceusters, Marc (January 2020). “Targeting neuroinflammation with brain penetrant P2X7 antagonists as novel therapeutics for neuropsychiatric disorders”. Neuropsychopharmacology. 45 (1): 234–235. doi:10.1038/s41386-019-0502-9. ISSN 0893-133X. PMC 6879571. PMID 31477815.

 Kolb, Hartmuth C.; Barret, Olivier; Bhattacharya, Anindya; Chen, Gang; Constantinescu, Cristian; Huang, Chaofeng; Letavic, Michael; Tamagnan, Gilles; Xia, Chunfang A.; Zhang, Wei; Szardenings, Anna Katrin (August 2019). “Preclinical Evaluation and Nonhuman Primate Receptor Occupancy Study of 18 F-JNJ-64413739, a PET Radioligand for P2X7 Receptors”. Journal of Nuclear Medicine. 60 (8): 1154–1159. doi:10.2967/jnumed.118.212696. ISSN 0161-5505. PMID 30733317. S2CID 73454130.

Clinical data
Trade names	Zanvipixant
Legal status
Legal status	Investigational New Drug
Identifiers
IUPAC name
CAS Number	2166558-11-6
PubChem CID	90408860
DrugBank	DB19110
ChemSpider	76771276
UNII	B7YN3CQ7S7
ChEMBL	ChEMBL3914857
Chemical and physical data
Formula	C17H12F5N7O
Molar mass	425.323 g·mol−1
3D model (JSmol)	Interactive image
SMILES
InChI

////////zanvipixant, ANAX LAB, purinoreceptor (P2X) antagonist, JNJ-55308942, JNJ 55308942, B7YN3CQ7S7,