Fosizensertib

CAS 2905377-00-4

MF C22H21F2N4O5P MW490.4 g/mol

[(2S)-1-[[5-[2-[1-(difluoromethyl)pyrazol-4-yl]ethynyl]pyridine-3-carbonyl]-methylamino]-3-phenylpropan-2-yl] dihydrogen phosphate

(2S)-1-(5-{[1-(difluoromethyl)-1H-pyrazol-4-yl]ethynyl}-Nmethylpyridine-3-carboxamido)-3-phenylpropan-2-yl dihydrogen
phosphate
receptor-interacting serine/threonine protein (RIP-1) kinase inhibitor, ABBV-668, ABBV 668, 6GA6XSX5SL

Fosizensertib (also known by the developmental code ABBV-668) is an investigational small molecule drug being evaluated for the treatment of ulcerative colitis and other chronic autoimmune or inflammatory conditions.

Mechanism of Action

• Target: It acts as a selective inhibitor of receptor-interacting serine/threonine-protein kinase 1 (RIPK1), an enzyme that plays a critical role in regulating cellular inflammation and necroptosis (programmed cell death).
• Prodrug Design: Fosizensertib functions as a phosphate prodrug. When administered, it is essentially inactive in vitro (inhibiting RIPK1 by less than 10%).
• Bioactivation: Once inside the body, it undergoes in vivo dephosphorylation to convert into its active metabolite (Compound 2), which strongly inhibits RIPK1 activity to suppress inflammatory pathways.

According to resources like the IUPHAR/BPS Guide to Pharmacology and PubChem, its core chemical metrics include:

Fosizensertib was assigned its International Nonproprietary Name (INN) by the World Health Organization (WHO). Developed by the pharmaceutical company AbbVie, it is classified as a clinical candidate intended for oral administration. It is currently restricted strictly to laboratory research and clinical evaluation settings and is not approved for general prescription or veterinary use.

PAT

[WO2023018643A1]

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=66762EE22EF5E77E0FC927179EB58712.wapp2nB?docId=WO2023018643&_cid=P21-MPOVCH-38336-1

(S)-1-(5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-N-methylnicotinamido)-3-phenylpropan-2-yl dihydrogen phosphate;

Examples #18 and 19: (S)–di–tert–butyl (1–(5–((1–(difluoromethyl)–1H–pyrazol–4– yl)ethynyl)–N–methylnicotinamido)–3–phenylpropan–2–yl) phosphate (Example #18) and (S)–1–(5–((1–(difluoromethyl)–1H–pyrazol–4–yl)ethynyl)–N–methylnicotinamido)–3– phenylpropan–2–yl dihydrogen phosphate (Example #19)

[0173] To a solution of (S)-5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-N-(2-hydroxy- 3-phenylpropyl)-N-methylnicotinamide (Example #2) (500 mg, 1.22 mmol) in N-Methyl-2- pyrrolidinone (1000 mL) was added di-tert-butyl diethylphosphoramidite (304 mg, 1.22 mmol) and 1H-tetrazole (10.8 mL, 4.87 mmol) in one portion at 20 °C under N₂. The mixture was stirred at 40 °C for 3 hours. Hydrogen peroxide (5.0 mL, 49 mmol) was added to the solution at 0 °C, and the mixture was stirred for an additional 2 hours. The mixture was poured into saturated Na2SO₃ (75 mL) and extracted with ethyl acetate (EtOAc) (3 × 100 mL). The organic phase was washed with brine (100 mL), dried over Na₂SO₄, concentrated under reduced pressure to give the crude t-butyl phosphate ester, which was chromatographed on silica gel (petroleum ether: ethyl acetate=1:1-1:4) to provide (S)-di-tert-butyl (1-(5-((1-(difluoromethyl)-1H-pyrazol-4- yl)ethynyl)-N-methylnicotinamido)-3-phenylpropan-2-yl) phosphate (Example #18) (384 mg, 0.64 mmol, 52% yield). LC/MS (Table B, Method aa) R_t = 1,73 min; MS m/z: 545.20 (M-tBu)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.76 – 8.40 (m, 3H), 8.15 – 7.60 (m, 3H), 7.27-7.01 (m, 5H), 4.78-4.46 (br m, 1H), 3.75-2.72 (m, 7H), 1.50-1.18 (m, 18H). tBu = tert–butyl; Et = ethyl.

[0174] A flask was charged with (S)-di-tert-butyl (1-(5-((1-(difluoromethyl)-1H-pyrazol-4- yl)ethynyl)-N-methylnicotinamido)-3-phenylpropan-2-yl) phosphate (Example #18) (381 mg, .632 mmol), dichloromethane (DCM) (5 mL) and trifluoroacetic acid (TFA) (0.61 mL, 7.9 mmol) and stirred at room temperature for approximately 19 hours. The mixture was concentrated under reduced pressure, then purified via reverse phase liquid chromatography (Atlantis^® Prep T3 Phenomenex 5 μm 19 x 50 mm column, 5 to 95 acetonitrile (MeCN):water (formic acid buffer) at 1 mL/minute) to provide the title compound, Example #19 (230 mg, 0.47 mmol, 74% yield). LC/MS (Table B, Method ff) R_t = 1.96 min; MS m/z: 491.0 (M+H)⁺; ¹H NMR (400 MHz,

DMSO-d₆) δ 8.78 – 8.69 (m, 1H), 8.65 – 8.57 (m, 1H), 8.44 (d, J = 1.0 Hz, 1H), 8.14 – 8.08 (m, 1H), 8.03 – 7.99 (m, 1H), 7.97 (s, 1H), 7.88 – 7.84 (m, 1H), 7.76 (s, 1H), 7.73 – 7.69 (m, 1H), 7.35 – 7.28 (m, 2H), 7.27 – 7.21 (m, 1H), 7.19 – 7.12 (m, 1H), 7.03 (br d, J = 7.5 Hz, 1H), 4.80 – 4.73 (m, 1H), 4.52 – 4.45 (m, 1H), 3.84 – 3.76 (m, 1H), 3.66 (br d, J = 13.5 Hz, 1H), 3.33 (br dd, J = 9.5, 13.5 Hz, 1H), 3.27 – 3.11 (m, 1H), 3.08 – 3.00 (m, 1H), 2.97 (s, 1H), 2.95 (br s, 1H), 2.92 (s, 2H), 2.90 – 2.85 (m, 1H), 2.79 – 2.69 (m, 1H), 2.07 (s, 1H), 1.78 (s, 1H), 1.74 (s, 1H).

ADVERTISEMENT

ANAX LABORATORIES

WEBSITE https://www.anaxlab.com/

Discovery Solutions, Supporting the chemistry needs of clients in the Medical, Analytical and Bio Sciences

Development Solutions, Developing from Lab scale to PR&D, Kilo Scale-ups and Commercial Scales

SEE MORE………Integrated Solutions, Manufacturing Solutions, Products,
Can’t Find? Let’s Connect

Phone : +91 897704 2010 /  +91 9177075735, Email : info@anaxlab.com

#MedicinalChemistry, #DrugDiscovery, #OrganicSynthesis, #ChemicalLibrary, #BuildingBlocks, #SARStudies, #ChemistryInnovation, #medchem, #Drugdevelopment, #Biotech, #Biotechnology, #AnaxLaboratories, #Pharma

AS ON FEB2026 4.574 LAKHS VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT

join me on Linkedin

Anthony Melvin Crasto Ph.D – India | LinkedIn

join me on Researchgate

RESEARCHGATE

join me on Facebook

Anthony Melvin Crasto Dr. | Facebook

• Twitter
• FACEBOOK

join me on twitter

Anthony Melvin Crasto Dr. | twitter

+919321316780 call whatsaapp

EMAIL. amcrasto@gmail.com

References

• Nicotinamide ripk1 inhibitorsPublication Number: WO-2023018643-A1Priority Date: 2021-08-10
• Nicotinamide ripk1 inhibitorsPublication Number: EP-4301744-A1Priority Date: 2021-08-10
• Nicotinamide RIPK1 inhibitorsPublication Number: US-11767310-B2Priority Date: 2021-08-10Grant Date: 2023-09-26
• Nicotinamide ripk1 inhibitorsPublication Number: US-2023127127-A1Priority Date: 2021-08-10

/////////fosizensertib, anax labs, ABBV-668, ABBV 668, 6GA6XSX5SL