Casdatifan

CAS 2709069-30-5

MF C21H17F4NO3S, 439.4 g/mol

(5R,6S,8R)-3,5,6-trifluoro-8-[(1S,2R)-2-fluoro-1-hydroxy-7-(methanesulfonyl)-2,3-dihydro-1H-inden-4-yl]-5,6,7,8-tetrahydronaphthalene-1-carbonitrile

(5R,6S,8R)-3,5,6-trifluoro-8-[(1S,2R)-2-fluoro-1-hydroxy-7-methylsulfonyl-2,3-dihydro-1H-inden-4-yl]-5,6,7,8-tetrahydronaphthalene-1-carbonitrile

(5R,6S,8R)-3,5,6-trifluoro-8-[(1S,2R)-2-fluoro-1-hydroxy-7-methylsulfonyl-2,3-dihydro-1H-inden-4-yl]-5,6,7,8-tetrahydronaphthalene-1-carbonitrile

(5R,6S,8R)-3,5,6-trifluoro-8-[(1S,2R)-2-fluoro-1-hydroxy-7-methanesulfonyl-2, 3-dihydro-1H-inden-4-yl]-5,6,7,8-tetrahydronaphthalene-1-carbonitrile
hypoxia-inducible factor (HIF) inhibitor, antineoplastic, AB 521, DP73UWL6LE

Casdatifan is an orally bioavailable allosteric inhibitor of hypoxia inducible factor (HIF)-2alpha, with potential antineoplastic activity. Upon oral administration, casdatifan targets and allosterically binds to a hydrophobic pocket on HIF-2alpha leading to a confirmational change that prevents HIF-2alpha heterodimerization with HIF-1beta and binding to the hypoxia response element (HRE) binding site on DNA. This results in decreased transcription and expression of HIF-2alpha downstream target genes, many of which regulate tumor cell growth and survival. Blocking HIF-2alpha reduces the proliferation of HIF-2alpha-expressing tumor cells. HIF-2alpha, a heterodimeric transcription factor overexpressed under hypoxic conditions in many cancer cell types, promotes proliferation, progression and metastasis of tumors.

• A Phase 1 Study of AB521 Monotherapy and Combination Therapies in Renal Cell Carcinoma and Other Solid TumorsCTID: NCT05536141Phase: Phase 1Status: RecruitingDate: 2026-01-02
• A Relative Bioavailability Study and Food Effect Study of AB521 in Healthy Adult VolunteersCTID: NCT05999513Phase: Phase 1Status: CompletedDate: 2024-10-17
• A Study to Investigate the Efficacy and Safety of Volrustomig ± Casdatifan vs Nivolumab + Ipilimumab as 1L Treatment for Advanced ccRCCCTID: NCT07000149Phase: Phase 3Status: Active, not recruitingDate: 2025-11-14
• Study of Zanzalintinib (XL092) + AB521 and Zanzalintinib + AB521 + Nivolumab in Participants With Advanced Clear Cell Renal Cell Carcinoma (ccRCC) or Other Advanced Solid Tumors (STELLAR-009)CTID: NCT06191796Phase: Phase 1Status: TerminatedDate: 2025-06-12
• Drug-Drug Interaction Study of Casdatifan in Healthy Adult Participants (ARC-29)CTID: NCT06919991Phase: Phase 1Status: CompletedDate: 2025-11-13

SYN

https://pubs.acs.org/doi/10.1021/acs.oprd.4c00497

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021188769&_cid=P12-MKDEE0-87371-1

Example 215: (5R,6S,8R)-3,5,6-trifluoro-8-[(1S,2R)-2-fluoro-1-hydroxy-7-methanesulfonyl-2, 3-dihydro-1H-inden-4-yl]-5,6,7,8-tetrahydronaphthalene-1-carbonitrile

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US442743749&_cid=P12-MKDEE0-87371-1

Example 2: Synthesis of (5R,6S,8R)-3,5,6-trifluoro-8-[(1S,2R)-2-fluoro-1-hydroxy-7-methanesulfonyl-2,3-dihydro-1H-inden-4-yl]-5,6,7,8-tetrahydronaphthalene-1-carbonitrile

Step i: Synthesis of Compound 11

Product 10 of step h (37.85 g, 78.28 mmol, 1.0 equiv.) was dissolved in THF (400 mL) at 23° C. A solution of hydrochloric acid (320 mL, 6M) was added dropwise over 20 min, and the mixture was stirred at 30° C. for 4 h. After this time, the reaction reached completion, as shown by LC/MS (MeCN/H ₂O—20%→100%, 6 min). The reaction mixture was diluted with water (1 L) and EtOAc (0.6 L), back-extracted twice with EtOAc, and washed with water, sat. sol. NaHCO ₃, and brine. The organic layer was dried over Na ₂SO ₄, filtered, and concentrated. The material (32.25 g, 94%) was triturated with CH ₂Cl ₂ (45 mL) at 45° C., filtered, and washed with a minimum of cold CH ₂Cl ₂ and cold hexanes to afford 11 as a white crystalline solid (26.15 g, 76%, 12:1 dr). ¹H NMR (400 MHZ, DMSO-d ₆) δ 7.96 (ddd, J=8.3, 2.7, 1.3 Hz, 1H), 7.89 (dd, J=8.9, 2.7 Hz, 1H), 7.57 (d, J=8.1 Hz, 1H), 6.66 (d, J=8.1 Hz, 1H), 5.95 (ddd, J=51.2, 13.5, 2.2 Hz, 1H), 5.89 (d, J=5.6 Hz, 1H), 5.47 (ddd, J=10.0, 6.2, 4.9 Hz, 1H), 5.26 (qd, J=52.5, 5.4 Hz, 1H), 5.12 (tddd, J=47.4, 18.7, 10.3, 2.7 Hz, 1H), 4.83 (t, J=5.4 Hz, 1H), 3.30 (s, 3H), 3.28-3.13 (m, 2H), 2.71-2.60 (m, 1H), 2.02-1.85 (m, 1H). ¹⁹F NMR (376 MHZ, DMSO-d ₆) δ −112.3, −179.6, −196.7, −199.4. ESI MS [M+Na] ⁺ for C ₂₁H ₁₇F ₄NO ₃SNa, calcd 462.0, found 461.9.

PAT

• Tetralin and tetrahydroquinoline compounds as inhibitors of hif-2alphaPublication Number: US-2023021476-A1Priority Date: 2020-03-19
• Tetralin and tetrahydroquinoline compounds as inhibitors of HIF-2αPublication Number: US-11407712-B2Priority Date: 2020-03-19Grant Date: 2022-08-09
• Tetralin and tetrahydroquinoline compounds as inhibitors of HIF-2alphaPublication Number: US-12103907-B2Priority Date: 2020-03-19Grant Date: 2024-10-01
• Tetralin and tetrahydroquinoline compounds as HIF-2α inhibitorsPublication Number: CN-115298165-APriority Date: 2020-03-19
• Tetralin and tetrahydroquinoline compounds as inhibitors of hif-2alphaPublication Number: US-2021317079-A1Priority Date: 2020-03-19
• Tetralin and tetrahydroquinoline compounds as inhibitors of hif-2alphaPublication Number: WO-2021188769-A1Priority Date: 2020-03-19
• Tetralin and tetrahydroquinoline compounds as inhibitors of hif-2alphaPublication Number: US-2024254079-A1Priority Date: 2020-03-19
• Process for preparing tetralin compoundsPublication Number: US-12145901-B1Priority Date: 2021-09-17Grant Date: 2024-11-19
• Tetralin and tetrahydroquinoline compounds as inhibitors of HIF-2alphaPublication Number: US-11787762-B2Priority Date: 2020-03-19Grant Date: 2023-10-17
• Tetrahydronaphthalene and tetrahydroquinoline compounds as HIF-2 alpha inhibitorsPublication Number: CN-119118872-APriority Date: 2020-03-19
• Tetralin and tetrahydroquinoline compounds as HIF-2α inhibitorsPublication Number: CN-115298165-BPriority Date: 2020-03-19Grant Date: 2024-09-17
• Tetralin and tetrahydroquinoline compounds as inhibitors of hif-2alphaPublication Number: US-2025214930-A1Priority Date: 2020-03-19

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////////Casdatifan, hypoxia-inducible factor (HIF) inhibitor, antineoplastic, AB 521, DP73UWL6LE