Vimseltinib

Vimseltinib

2/14/2025 FDA APPROVED, Romvimza

3-methyl-5-[6-methyl-5-[2-(1-methylpyrazol-4-yl)pyridin-4-yl]oxypyridin-2-yl]-2-(propan-2-ylamino)pyrimidin-4-one

C₂₃H₂₅N₇O₂, 431.5

• DP-6865
• PX9FTM69BF
• DCC3014
• UNII-PX9FTM69BF
• WHO 11443
• 
  DCC-3014
• DP-6865

To treat symptomatic tenosynovial giant cell tumor for which surgical resection will potentially cause worsening functional limitation or severe morbidity

Vimseltinib is an orally bioavailable inhibitor of the tyrosine kinase receptor colony stimulating factor 1 receptor (CSF1R; CSF-1R; C-FMS; CD115; M-CSFR), with potential antineoplastic, macrophage checkpoint-inhibitory and immunomodulating activities. Upon administration, vimseltinib targets and binds to CSF1R expressed on monocytes, macrophages, and osteoclasts and inhibits the binding of the CSF1R ligands colony-stimulating factor-1 (CSF-1) and interleukin-34 (IL-34), to CSF1R. This prevents CSF1R activation and CSF1R-mediated signaling in these cells. This blocks the production of inflammatory mediators by macrophages and monocytes and reduces inflammation. By blocking the recruitment to the tumor microenvironment (TME) and activity of CSF1R-dependent tumor-associated macrophages (TAMs), vimseltinib inhibits the immunomodulating activity by macrophages and enhances T-cell infiltration and anti-tumor T-cell immune responses, which inhibits the proliferation of tumor cells. TAMs play key roles in the TME and allow for immune suppression; TAMs promote inflammation, tumor cell proliferation, angiogenesis, invasiveness and survival.

Vimseltinib, sold under the brand name Romvimza, is an anti-cancer medication used for the treatment of tenosynovial giant cell tumor.^[1][2] Vimseltinib is a kinase inhibitor.^[1][2] Vimseltinib is a macrophage colony-stimulating factor receptor antagonist.^[3]

The most common adverse reactions, including laboratory abnormalities, include increased aspartate aminotransferase, periorbital edema, fatigue, rash, increased cholesterol, peripheral edema, face edema, decreased neutrophils, decreased leukocytes, pruritus, and increased alanine aminotransferase.^[2]

Vimseltinib was approved for medical use in the United States in February 2025.^[2][4]

PATENT

vimseltinib is a c-FMS (CSF-IR) and c-KIT dual inhibitor with anticancer and antiproliferative activities, can excite tyrosine protein kinase activity, influence protooncogene transcription, and is widely applied to research of anticancer drugs as an active molecule.

CN105120864B discloses heating the reaction mixture in a sealed tube at 100 ℃ for 2 days. The mixture was then cooled to room temperature, the solids were removed by filtration and the filtrate was concentrated to dryness and purified by silica gel chromatography to give 2- (isopropylamino) -3-methyl-5- (6-methyl-5- ((2- (1-methyl-1H-pyrazol-4-yl) pyridin-4-yl) oxy) pyridin-2-yl) pyrimidin-4 (3H) -one, amorphous form described.

CN113880812a reports another preparation method of Vimseltinib, and a small amount of target product meeting the requirement is finally obtained through a column chromatography purification process. The preparation method has complicated process and is not beneficial to industrialized mass production. There is no mention in this patent of reports on solid or crystalline forms of the compound of formula (I), and the purification process of column chromatography (EA/meoh=120:1 to 100:1) was repeated to give form a.

CN116283919A

https://patents.google.com/patent/CN116283919A/en

PATENT

example 10 [WO2014145025A2]

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014145025&_cid=P21-M98JKR-94364-1

Example 2: A solution of Example C2 (0.13 g, 0.309 mmol) in DCM (5 mL) was treated portion-wise with mCPBA (0.09 g, 0.37 mmol), stirred at RT overnight, treated with TEA (0.5 mL) and Ν,Ν-dimethylamine HCl salt (500 mg) and stirred at RT for 2 h. The mixture was treated with satd. NaHCO₃, extracted with DCM (2x) and the combined organics were dried over Na₂SO₄, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to obtain 4-methoxy-N,N-dimethyl-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-2-amine (60 mg, 47%). MS (ESI) m/z: 418.2 (M+H⁺).

[0199] A solution of 4-methoxy-N,N-dimethyl-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-2-amine (0.060 g, 0.144 mmol) in acetic acid (5 mL) was treated with HBr (0.065 mL, 0.575 mmol), heated at 90°C for 6 h, cooled to RT and quenched with ice water. The solution was treated with NaHCO₃ and NaCl, extracted with 1 : 1 THF/EtOAc (3x) and the combined organics were dried over Na₂SO₄ and concentrated to dryness. The material was treated with MeCN (1 mL), allowed to stand at RT and the

resulting solid was collected via filtration to afford 2-(dimethylamino)-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one (43 mg, 71%). ¹H NMR (400 MHz, DMSO-d₆): δ 11.23 (s, 1 H), 8.73 (s, 1 H), 8.36 (d, J = 5.7 Hz, 1 H), 8.30 (m, 1H), 8.26 (s, 1 H), 7.97 (s, 1 H), 7.51 (m, 1H), 7.23 (d, J = 2.4 Hz, 1 H), 6.62 (br s, 1 H), 3.85 (s, 3 H), 3.12 (s, 6 H), 2.35 (s, 3 H); MS (ESI) m/z: 404.2 (M+H⁺).

Example 3: A solution of Example C2 (0.13 g, 0.309 mmol) in DCM (5 mL) was treated portion-wise with mCPBA (0.09 g, 0.37 mmol), stirred at RT overnight, treated with isopropyl amine (0.5 mL) and stirred at RT overnight. The mixture was treated with satd. NaHCO₃, extracted with DCM (2x) and the combined organics were dried over Na₂SO₄, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to obtain N-isopropyl-4-methoxy-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-2-amine (63 mg, 47%). MS (ESI) m/z: 432.2 (M+H⁺).

PAPER

Discovery of vimseltinib (DCC-3014), a highly selective CSF1R switch-control kinase inhibitor, in clinical development for the treatment of Tenosynovial Giant Cell Tumor (TGCT)

https://www.sciencedirect.com/science/article/pii/S0960894X22004048

Medical uses

Vimseltinib is indicated for the treatment of adults with symptomatic tenosynovial giant cell tumor for which surgical resection will potentially cause worsening functional limitation or severe morbidity.^[1][2]

History

The efficacy of vimseltinib was evaluated in MOTION (NCT05059262), a double-blind, multicenter, randomized (2:1), placebo-controlled trial in participants with tenosynovial giant cell tumor for whom surgical resection may cause worsening functional limitation or severe morbidity.^[2] Eligible participants had a confirmed diagnosis of tenosynovial giant cell tumor with measurable disease (RECIST v1.1) with at least one lesion having a minimum size of 2 cm.^[2] Pp[-[p;articipants were randomized to placebo or vimseltinib, 30 mg twice weekly administered for 24 weeks, during the double-blind period (part 1).^[2] During the open-label period (part 2), patients could continue vimseltinib and those receiving placebos could crossover to vimseltinib.^[2] Randomization was stratified by tumor location (lower limb versus all other) and region (United States versus Non-US).^[2] A total of 123 participants were randomized: 83 to the vimseltinib arm and 40 to placebo during part 1.^[2]

The US. Food and Drug Administration (FDA) granted the application for vimseltinib priority review designation.^[2]

Society and culture

Legal status

Vimseltinib was approved for medical use in the United States in February 2025.^[2][5]

Names

Vimseltinib is the international nonproprietary name.^[6]

Vimseltinib is sold under the brand name Romvimza.^[1][2]

References

1. ^ Jump up to:^{a b c d e} “Romvimza- vimseltinib capsule”. DailyMed. 18 February 2025. Retrieved 3 March 2025.
2. ^ Jump up to:^{a b c d e f g h i j k l m n} “FDA approves vimseltinib for symptomatic tenosynovial giant cell tumor”. U.S. Food and Drug Administration (FDA). 14 February 2025. Retrieved 16 February 2025.  This article incorporates text from this source, which is in the public domain.
3. ^ Caldwell TM, Ahn YM, Bulfer SL, Leary CB, Hood MM, Lu WP, et al. (October 2022). “Discovery of vimseltinib (DCC-3014), a highly selective CSF1R switch-control kinase inhibitor, in clinical development for the treatment of Tenosynovial Giant Cell Tumor (TGCT)”. Bioorganic & Medicinal Chemistry Letters. 74: 128928. doi:10.1016/j.bmcl.2022.128928. PMID 35961460.
4. ^ “Novel Drug Approvals for 2025”. U.S. Food and Drug Administration (FDA). 21 February 2025. Retrieved 9 March 2025.
5. ^ “U.S. FDA Grants Full Approval of Deciphera’s Romvimza (vimseltinib) for the Treatment of Symptomatic Tenosynovial Giant Cell Tumor (TGCT)” (Press release). Deciphera Pharmaceuticals. 14 February 2025. Retrieved 16 February 2025 – via Business Wire.
6. ^ World Health Organization (2021). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 85”. WHO Drug Information. 35 (1). hdl:10665/340684.

External links

• Clinical trial number NCT05059262 for “Study of Vimseltinib for Tenosynovial Giant Cell Tumor (MOTION)” at ClinicalTrials.gov

1. Caldwell TM, Ahn YM, Bulfer SL, Leary CB, Hood MM, Lu WP, Vogeti L, Vogeti S, Kaufman MD, Wise SC, Le Bourdonnec B, Smith BD, Flynn DL: Discovery of vimseltinib (DCC-3014), a highly selective CSF1R switch-control kinase inhibitor, in clinical development for the treatment of Tenosynovial Giant Cell Tumor (TGCT). Bioorg Med Chem Lett. 2022 Oct 15;74:128928. doi: 10.1016/j.bmcl.2022.128928. Epub 2022 Aug 10. [Article]
2. Smith BD, Kaufman MD, Wise SC, Ahn YM, Caldwell TM, Leary CB, Lu WP, Tan G, Vogeti L, Vogeti S, Wilky BA, Davis LE, Sharma M, Ruiz-Soto R, Flynn DL: Vimseltinib: A Precision CSF1R Therapy for Tenosynovial Giant Cell Tumors and Diseases Promoted by Macrophages. Mol Cancer Ther. 2021 Nov;20(11):2098-2109. doi: 10.1158/1535-7163.MCT-21-0361. Epub 2021 Aug 25. [Article]
3. FDA Approved Drug Products: Romvimza (vimseltinib) capsules for oral use (February 2025) [Link]
4. FDA News Release: FDA approves vimseltinib for symptomatic tenosynovial giant cell tumor [Link]

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UNII-PX9FTM69BF