Deuruxolitinib

C₁₇H₁₈N₆, 314.422

Fda approved Leqselvi, 7/25/2024, To treat severe alopecia areata

C-21543, CTP 543, CTP-543, CTP543

(3r)-3-(2,2,3,3,4,4,5,5-d8)cyclopentyl-3-(4-(7h-pyrrolo(2,3-d)pyrimidin-4-yl)-1h-pyrazol-1-yl)propanenitrile

1h-pyrazole-1-propanenitrile, .beta.-(cyclopentyl-2,2,3,3,4,4,5,5-d8)-4-(7h-pyrrolo(2,3-d)pyrimidin-4-yl)-, (.beta.r)-D8-ruxolitinib

Ingredient	UNII	CAS	InChI Key
Deuruxolitinib phosphate	8VJ43S4LCM	2147706-60-1	JFMWPOCYMYGEDM-NTVOUFPTSA-N

unii
0CA0VSF91Y

Deuruxolitinib, sold under the brand name Leqselvi, is a medication used for the treatment of alopecia areata.^[1] It is a Janus kinase inhibitor selective for JAK1 and JAK2.^[2] Although the relative effectiveness of deuruxolitinib and another Janus kinase inhibitor—baricitinib—for alopecia areata may vary depending on the population studied, both drugs are more effective than alternative treatments.^[3]

Deuruxolitinib was approved for medical use in the United States in July 2024.^[1][4]

Medical uses

Deuruxolitinib is indicated for the treatment of adults with severe alopecia areata.^[1]

Side effects

The FDA prescribing label for deuruxolitinib contains a boxed warning for serious infections; malignancies; cardiovascular death, myocardial infarction, and stroke; and thrombosis.^[5]

Society and culture

Names

Deuruxolitinib is the international nonproprietary name^[6] and the United States Adopted Name.^[7]

SYN

20240108633METHOD FOR PREVENTING OR TREATING DISEASE OR CONDITION ASSOCIATED WITH ANTITUMOR AGENT

20240058345TREATMENT OF HAIR LOSS DISORDERS WITH DEUTERATED JAK INHIBITORS

2023553253重水素化ＪＡＫ阻害剤による脱毛障害の治療のためのレジメン

20230390292REGIMENS FOR THE TREATMENT OF HAIR LOSS DISORDERS WITH DEUTERATED JAK INHIBITORS

20230322787PROCESS FOR PREPARING ENANTIOMERICALLY ENRICHED JAK INHIBITORS

1020230093504중수소화된 JAK 억제제를 이용한 탈모 장애의 치료를 위한 요법

WO/2023/018954TREATMENT OF JAK-INHIBITION-RESPONSIVE DISORDERS WITH PRODRUGS OF JAK INHIBITORS

2022171838TREATMENT OF ALOPECIA CAUSED BY DEUTERATED JAK INHIBITOR

2022171838TREATMENT OF ALOPECIA CAUSED BY DEUTERATED JAK INHIBITOR

20220226327Combination therapy comprising JAK pathway inhibitor and rock inhibitor

20220213105PROCESS FOR PREPARING ENANTIOMERICALLY ENRICHED JAK INHIBITORS

20220202834JAK inhibitor with a vitamin D analog for treatment of skin diseases

20210387991Deuterated JAK inhibitor and uses thereof SUN

WO/2020/163653PROCESS FOR PREPARING ENANTIOMERICALLY ENRICHED JAK INHIBITORS CONCERT

20200222408TREATMENT OF HAIR LOSS DISORDERS WITH DEUTERATED JAK INHIBITORS

2019516684Treatment of Hair Loss Disorders with Deuterated JAK Inhibitors

PATENT

US20210387991

USE OF COMPD NOT SYNTHESIS

https://patentscope.wipo.int/search/en/detail.jsf?docId=US344953814&_cid=P12-M0XGHQ-19840-2

Example 1

Synthesis of Compound 10

The synthesis of Compound 10, or a pharmaceutically acceptable salt thereof (such as the phosphate salt) may be readily achieved, e.g., reaction of CTP-543 under conditions suitable to provide hydrolysis of the nitrile functionality of CTP-543. CTP-543 can be prepared, e.g., according to the methods described in U.S. Pat. No. 9,249,149 and US Patent Pub. No. 2019/0160068 (the teachings of which are incorporated herein by reference), to produce CTP-543 and/or its phosphate salt. CTP-543 phosphate salt may be transformed into Compound 10 or its phosphate salt according to Scheme 1 below.

To a round bottom flask, equipped with a magnetic stir bar, was charged sulfuric acid (2 mL) followed by careful addition of CTP-543 Phosphate (4.05 g, 9.8 mmol). To the mixture was added another portion of sulfuric acid (2 mL) and water (0.8 mL). The reaction was stirred at room temperature for 4 hours, then quenched by addition of a potassium carbonate solution (80 g, 30% w/w). The product was extracted using isopropyl alcohol. The organic phase was concentrated under vacuum to dryness. The product was dissolved in isopropyl alcohol (100 mL) and phosphoric acid (1 mL, 85% w/w) was added to crystallize the product as the phosphate salt. The precipitate was filtered and dried in a vacuum oven (5 torr, room temp, slight nitrogen purge) to yield the desired compound as an off-white solid (1.82 g, 4.2 mmol, 43% yield). The product was analyzed by HPLC, HRMS, and NMR.

1H-NMR (400 MHz, DMSO-d 6): δ 12.05 (s, 1H), 8.64 (s, 1H), 8.56 (d, J=0.9 Hz, 1H), 8.26 (s, 1H), 7.55 (dd, J=3.6, 2.3 Hz, 1H), 7.33 (s, 1H), 6.96 (dd, J=3.6, 1.6 Hz, 1H), 6.76 (s, 1H), 4.57 (td, J=9.7, 4.0 Hz, 1H), 2.88 (dd, J=15.3, 10.0 Hz, 1H), 2.64 (dd, J=15.3, 4.0 Hz, 1H), 2.32 (d, J=9.3 Hz, 1H).

HPLC method summary: column=Waters XBridge C18, 4.6×150 mm, 3.5 μm column; gradient elution: mobile phase A=10 mM ammonium formate, pH 3.9; mobile phase B=acetonitrile; detection=ultraviolet absorbance at 254 nm. Result: Compound (I)=98.7 area %; retention time=11.1 min.

HRMS: Agilent 6530 Q-TOF LC/MS system with electrospray ionization in positive mode. The measured time-of-flight mass-to-charge ratio (m/z) is 333.22839 (theoretical value=333.22735).

Clinical data
Trade names	Leqselvi
Other names	CTP-543
License data	US DailyMed: Deuruxolitinib
Routes of administration	By mouth
Drug class	Janus kinase inhibitor
ATC code	None
Legal status
Legal status	US: ℞-only[1]
Identifiers
showIUPAC name
CAS Number	1513883-39-0as phosphate: 2147706-60-1
PubChem CID	72704611as phosphate: 154572727
DrugBank	DB18847
ChemSpider	115010950
UNII	0CA0VSF91Yas phosphate: 8VJ43S4LCM
KEGG	D11866as phosphate: D11867
ChEMBL	ChEMBL4594381
Chemical and physical data
Formula	C17H18N6
Molar mass	306.373 g·mol−1
3D model (JSmol)	Interactive image
showSMILES

References

King B, Mesinkovska N, Mirmirani P, Bruce S, Kempers S, Guttman-Yassky E, Roberts JL, McMichael A, Colavincenzo M, Hamilton C, Braman V, Cassella JV: Phase 2 randomized, dose-ranging trial of CTP-543, a selective Janus Kinase inhibitor, in moderate-to-severe alopecia areata. J Am Acad Dermatol. 2022 Aug;87(2):306-313. doi: 10.1016/j.jaad.2022.03.045. Epub 2022 Mar 29. [Article]Yan T, Wang T, Tang M, Liu N: Comparative efficacy and safety of JAK inhibitors in the treatment of moderate-to-severe alopecia areata: a systematic review and network meta-analysis. Front Pharmacol. 2024 Apr 10;15:1372810. doi: 10.3389/fphar.2024.1372810. eCollection 2024. [Article]Barati Sedeh F, Michaelsdottir TE, Henning MAS, Jemec GBE, Ibler KS: Comparative Efficacy and Safety of Janus Kinase Inhibitors Used in Alopecia Areata: A Systematic Review and Meta-analysis. Acta Derm Venereol. 2023 Jan 25;103:adv00855. doi: 10.2340/actadv.v103.4536. [Article]Sardana K, Bathula S, Khurana A: Which is the Ideal JAK Inhibitor for Alopecia Areata – Baricitinib, Tofacitinib, Ritlecitinib or Ifidancitinib – Revisiting the Immunomechanisms of the JAK Pathway. Indian Dermatol Online J. 2023 Jun 28;14(4):465-474. doi: 10.4103/idoj.idoj_452_22. eCollection 2023 Jul-Aug. [Article]FDA Approved Drug Products: LEQSELVI (deuruxolitinib) tablets, for oral use [Link]AJMC: FDA Approves Deuruxolitinib for Alopecia Areata [Link]

^ Jump up to:^a b c d “Archived copy” (PDF). Archived (PDF) from the original on 29 July 2024. Retrieved 26 July 2024.

1. ^ King, Brett; Mesinkovska, Natasha; Mirmirani, Paradi; Bruce, Suzanne; Kempers, Steve; Guttman-Yassky, Emma; et al. (August 2022). “Phase 2 randomized, dose-ranging trial of CTP-543, a selective Janus Kinase inhibitor, in moderate-to-severe alopecia areata”. Journal of the American Academy of Dermatology. 87 (2): 306–313. doi:10.1016/j.jaad.2022.03.045. ISSN 1097-6787. PMID 35364216. S2CID 247866262.
2. ^ SEDEH, Farnam Barati; MICHAELSDÓTTIR, Thorunn Elísabet; HENNING, Mattias Arvid Simon; JEMEC, Gregor Borut Ernst; IBLER, Kristina Sophie (25 January 2023). “Comparative Efficacy and Safety of Janus Kinase Inhibitors Used in Alopecia Areata: A Systematic Review and Meta-analysis”. Acta Dermato-Venereologica. 103: 4536. doi:10.2340/actadv.v103.4536. ISSN 0001-5555. PMC 10391778. PMID 36695751.
3. ^ “U.S. FDA Approves Leqselvi (deuruxolitinib), an Oral JAK Inhibitor for the Treatment of Severe Alopecia Areata” (Press release). Sun Pharmaceutical. 25 July 2024. Archived from the original on 26 July 2024. Retrieved 26 July 2024 – via PR Newswire.
4. ^ http://www.leqselvi.com/&a=Prescribing Information
5. ^ World Health Organization (2021). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 86”. WHO Drug Information. 35 (3). hdl:10665/346562.
6. ^ “Deuruxolitinib”. American Medical Association. Retrieved 27 July 2024.

Further reading

Passeron T, King B, Seneschal J, Steinhoff M, Jabbari A, Ohyama M, et al. (2023). “Inhibition of T-cell activity in alopecia areata: recent developments and new directions”. Frontiers in Immunology. 14: 1243556. doi:10.3389/fimmu.2023.1243556. PMC 10657858. PMID 38022501.

External links

• “Deuruxolitinib (Code C175770)”. NCI Thesaurus.
• “Deuruxolitinib Phosphate (Code C175771)”. NCI Thesaurus.
• Clinical trial number NCT04518995 for “Study to Evaluate the Efficacy and Safety of CTP-543 in Adults With Moderate to Severe Alopecia Areata (THRIVE-AA1) (THRIVE-AA1)” at ClinicalTrials.gov
• Clinical trial number NCT04797650 for “Study to Evaluate the Efficacy and Safety of CTP-543 in Adults With Moderate to Severe Alopecia Areata (THRIVE-AA2) (THRIVE-AA2)” at ClinicalTrials.gov

////Deuruxolitinib, alopecia areata, Leqselvi , approvals 2024, fda 2024, C-21543, CTP 543, CTP-543, CTP543, UNII-0CA0VSF91Y, WHO 11622