Ibrexafungerp citrate
アイブレキサフンジェルプクエン酸塩;
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Formula |
C44H67N5O4. C6H8O7
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cas |
1965291-08-0
free 1207753-03-4
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Mol weight |
922.1574
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Brexafemme, fda approved 2021, 2021/6/1
Antifungal, Cell wall biosynthesis inhibitor, Treatment of invasive fungal infections due to Candida spp. or Aspergillus spp., vulvovaginal candidiasis
SCY-078 citrate, MK-3118; SCY-078,
- WHO 10597
(1R,5S,6R,7R,10R,11R,14R,15S,20R,21R)-21-[(2R)-2-amino-2,3,3-trimethylbutoxy]-5,7,10,15-tetramethyl-7-[(2R)-3-methylbutan-2-yl]-20-(5-pyridin-4-yl-1,2,4-triazol-1-yl)-17-oxapentacyclo[13.3.3.01,14.02,11.05,10]henicos-2-ene-6-carboxylic acid;2-hydroxypropane-1,2,3-tricarboxylic acid
- Originator Merck & Co; SCYNEXIS
- Class Antifungals; Glycosides; Triterpenes
- Mechanism of ActionBeta-1,3-D glucan synthetase inhibitors
- Orphan Drug StatusYes – Invasive bronchopulmonary aspergillosis; Candidiasis
- RegisteredVulvovaginal candidiasis
- Phase IIICandidiasis
- Phase IIInvasive bronchopulmonary aspergillosis
- Phase IUnspecified
- PreclinicalPneumocystis pneumonia
- 01 Jun 2021Registered for Vulvovaginal candidiasis (In adolescents, In children, In the elderly, In adults) in USA (PO)
- 01 May 2021Ibrexafungerp – SCYNEXIS receives Qualified Infectious Disease Product status for Vulvovaginal candidiasis (Recurrent, Prevention) in USA
- 30 Apr 2021Efficacy data from phase III VANISH-303 and VANISH-306 trials in Vulvovaginal Candidiasis presented at the 2021 American College of Obstetricians and Gynecologists Annual Meeting (ACOG-2021)
Ibrexafungerp, sold under the brand name Brexafemme, is an antifungal medication used to treat vulvovaginal candidiasis (VVC) (vaginal yeast infection).[1] It is taken by mouth.[1]
Ibrexafungerp is a triterpenoid antifungal.[1]
Ibrexafungerp was approved for medical use in the United States in June 2021.[1][2] It is the first approved drug in a novel antifungal class.[2]
Medical uses
Ibrexafungerp is indicated for the treatment of adult and postmenarchal pediatric females with vulvovaginal candidiasis (VVC).[1][2]
Syn
https://www.sciencedirect.com/science/article/abs/pii/S0960894X20307721
Abstract
We previously reported medicinal chemistry efforts that identified MK-5204, an orally efficacious β-1,3-glucan synthesis inhibitor derived from the natural product enfumafungin. Further extensive optimization of the C2 triazole substituent identified 4-pyridyl as the preferred replacement for the carboxamide of MK-5204, leading to improvements in antifungal activity in the presence of serum, and increased oral exposure. Reoptimizing the aminoether at C3 in the presence of this newly discovered C2 substituent, confirmed that the (R) t-butyl, methyl aminoether of MK-5204 provided the best balance of these two key parameters, culminating in the discovery of ibrexafungerp, which is currently in phase III clinical trials. Ibrexafungerp displayed significantly improved oral efficacy in murine infection models, making it a superior candidate for clinical development as an oral treatment for Candida and Aspergillus infections.
References
- ^ Jump up to:a b c d e f g https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214900s000lbl.pdf
- ^ Jump up to:a b c “Scynexis Announces FDA Approval of Brexafemme (ibrexafungerp tablets) as the First and Only Oral Non-Azole Treatment for Vaginal Yeast Infections”. Scynexis, Inc. (Press release). 2 June 2021. Retrieved 2 June 2021.
Further reading
- Azie N, Angulo D, Dehn B, Sobel JD (September 2020). “Oral Ibrexafungerp: an investigational agent for the treatment of vulvovaginal candidiasis”. Expert Opin Investig Drugs. 29 (9): 893–900. doi:10.1080/13543784.2020.1791820. PMID 32746636.
- Davis MR, Donnelley MA, Thompson GR (July 2020). “Ibrexafungerp: A novel oral glucan synthase inhibitor”. Med Mycol. 58 (5): 579–592. doi:10.1093/mmy/myz083. PMID 31342066.
- Petraitis V, Petraitiene R, Katragkou A, Maung BB, Naing E, Kavaliauskas P, et al. (May 2020). “Combination Therapy with Ibrexafungerp (Formerly SCY-078), a First-in-Class Triterpenoid Inhibitor of (1→3)-β-d-Glucan Synthesis, and Isavuconazole for Treatment of Experimental Invasive Pulmonary Aspergillosis”. Antimicrob Agents Chemother. 64 (6). doi:10.1128/AAC.02429-19. PMC 7269506. PMID 32179521.
External links
- “Ibrexafungerp”. Drug Information Portal. U.S. National Library of Medicine.
- Clinical trial number NCT03734991 for “Efficacy and Safety of Oral Ibrexafungerp (SCY-078) vs. Placebo in Subjects With Acute Vulvovaginal Candidiasis (VANISH 303)” at ClinicalTrials.gov
- Clinical trial number NCT03987620 for “Efficacy and Safety of Oral Ibrexafungerp (SCY-078) vs. Placebo in Subjects With Acute Vulvovaginal Candidiasis (Vanish 306)” at ClinicalTrials.gov
Ibrexafungerp, also known as SCY-078 or MK-3118, is a novel enfumafungin derivative oral triterpene antifungal approved for the treatment of vulvovaginal candidiasis (VVC), also known as a vaginal yeast infection.1,9 It was developed out of a need to treat fungal infections that may have become resistant to echinocandins or azole antifungals.1 Ibrexafungerp is orally bioavailable compared to the echinocandins caspofungin, micafungin, and anidulafungin; which can only be administered parenterally.1,2 Similar to echinocandins, ibrexafungerp targets the fungal β-1,3-glucan synthase, which is not present in humans, limiting the chance of renal or hepatic toxicity.6,9
Ibrexafungerp was granted FDA approval on 1 June 2021.9
β-1,3-glucan synthase is composed of a catalytic subunit, FKS1 or FKS2, and a GTP-binding regulatory subunit, Rho1.5,6 This synthase is involved in the synthesis of β-1,3-glucan, a fungal cell wall component.6
Ibrexafungerp acts similarly to the echinocandin antifungals, by inhibiting the synthesis of β-1,3-glucan synthase.1,9 While echinocandins bind to the FKS1 domain of β-1,3-glucan synthase, enfumafungin and its derivatives bind at an alternate site which allows them to maintain their activity against fungal infections that are resistant to echinocandins.3,4
Ibrexafungerp has been shown in animal studies to distribute well to vaginal tissue, making it a favourable treatment for vulvovaginal candidiasis.4
- Wring SA, Randolph R, Park S, Abruzzo G, Chen Q, Flattery A, Garrett G, Peel M, Outcalt R, Powell K, Trucksis M, Angulo D, Borroto-Esoda K: Preclinical Pharmacokinetics and Pharmacodynamic Target of SCY-078, a First-in-Class Orally Active Antifungal Glucan Synthesis Inhibitor, in Murine Models of Disseminated Candidiasis. Antimicrob Agents Chemother. 2017 Mar 24;61(4). pii: AAC.02068-16. doi: 10.1128/AAC.02068-16. Print 2017 Apr. [Article]
- Hector RF, Bierer DE: New beta-glucan inhibitors as antifungal drugs. Expert Opin Ther Pat. 2011 Oct;21(10):1597-610. doi: 10.1517/13543776.2011.603899. Epub 2011 Jul 25. [Article]
- Kuhnert E, Li Y, Lan N, Yue Q, Chen L, Cox RJ, An Z, Yokoyama K, Bills GF: Enfumafungin synthase represents a novel lineage of fungal triterpene cyclases. Environ Microbiol. 2018 Sep;20(9):3325-3342. doi: 10.1111/1462-2920.14333. Epub 2018 Sep 13. [Article]
- Larkin EL, Long L, Isham N, Borroto-Esoda K, Barat S, Angulo D, Wring S, Ghannoum M: A Novel 1,3-Beta-d-Glucan Inhibitor, Ibrexafungerp (Formerly SCY-078), Shows Potent Activity in the Lower pH Environment of Vulvovaginitis. Antimicrob Agents Chemother. 2019 Apr 25;63(5). pii: AAC.02611-18. doi: 10.1128/AAC.02611-18. Print 2019 May. [Article]
- Ha YS, Covert SF, Momany M: FsFKS1, the 1,3-beta-glucan synthase from the caspofungin-resistant fungus Fusarium solani. Eukaryot Cell. 2006 Jul;5(7):1036-42. doi: 10.1128/EC.00030-06. [Article]
- Perlin DS: Mechanisms of echinocandin antifungal drug resistance. Ann N Y Acad Sci. 2015 Sep;1354:1-11. doi: 10.1111/nyas.12831. Epub 2015 Jul 17. [Article]
- Wring S, Murphy G, Atiee G, Corr C, Hyman M, Willett M, Angulo D: Clinical Pharmacokinetics and Drug-Drug Interaction Potential for Coadministered SCY-078, an Oral Fungicidal Glucan Synthase Inhibitor, and Tacrolimus. Clin Pharmacol Drug Dev. 2019 Jan;8(1):60-69. doi: 10.1002/cpdd.588. Epub 2018 Jun 27. [Article]
- Ghannoum M, Arendrup MC, Chaturvedi VP, Lockhart SR, McCormick TS, Chaturvedi S, Berkow EL, Juneja D, Tarai B, Azie N, Angulo D, Walsh TJ: Ibrexafungerp: A Novel Oral Triterpenoid Antifungal in Development for the Treatment of Candida auris Infections. Antibiotics (Basel). 2020 Aug 25;9(9). pii: antibiotics9090539. doi: 10.3390/antibiotics9090539. [Article]
- FDA Approved Drug Products: Brexafemme (Ibrexafungerp) Oral Tablet [Link]
Clinical data | |
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Trade names | Brexafemme |
Other names | SCY-078 |
License data | |
Pregnancy category |
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Routes of administration |
By mouth |
Drug class | Antifungal |
ATC code |
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Legal status | |
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Identifiers | |
CAS Number |
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PubChem CID | |
UNII | |
KEGG | |
ChEMBL |
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Chemical and physical data | |
Formula | C44H67N5O4 |
Molar mass | 730.051 g·mol−1 |
3D model (JSmol) | |
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/////////Ibrexafungerp citrate, Brexafemme, アイブレキサフンジェルプクエン酸塩 , SCY-078 citrate, UNII-M4NU2SDX3E, M4NU2SDX3E, MK-3118; SCY-078, Orphan Drug, Merck, SCYNEXIS, WHO 10597, ANTI FUNGAL
CC(C)C(C)C1(CCC2(C3CCC4C5(COCC4(C3=CCC2(C1C(=O)O)C)CC(C5OCC(C)(C(C)(C)C)N)N6C(=NC=N6)C7=CC=NC=C7)C)C)C.C(C(=O)O)C(CC(=O)O)(C(=O)O)O