Ibrexafungerp citrate

アイブレキサフンジェルプクエン酸塩;

Formula	C44H67N5O4. C6H8O7
cas	Citrate1965291-08-0 free 1207753-03-4
Mol weight	922.1574

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

UNII-M4NU2SDX3E

M4NU2SDX3E

(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[13.3.3.0^1,14.0^2,11.0^5,10]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.

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SYN

Bioorg. Med. Chem. Lett. 2021, 32, 127661.

PATENT

WO 2010019204

https://patents.google.com/patent/WO2010019204A1/en

SYN

https://doi.org/10.1021/acs.jmedchem.3c00501

Ibrexafungerp (Brexafemme). Ibrexafungerp (1), formerly SCY-078 or MK-3118 and developed by Scynexis Inc., is a first-in-class triterpenoid antifungal that inhibits the biosynthesis of β-(1,3)
D-glucan in the fungal cell wall. This mechanism of action provides an opportunity for the treatment
of fungal infections that are azole- or echinocandrin-resistant strains. In June 2021, ibrexafungerp received its first approval by the United States Food and Drug Administration (USFDA) for
the treatment of vulvovaginal candidiasis in adult and postmenarchal pediatric females.
24,25 Ibrexafungerp is a semisynthetic derivative of the natural product enfumafungin that
incorporates a pyridine triazole moiety on the core phenanthropyran ring system as well as a pendant 2-amino-2,3,3trimethyl-butyl ether. The drug demonstrates potent, broad spectrum activity against Candida sp. and is orally bioavailable.
As shown in Scheme 1, the synthesis of ibrexafungerp started with the natural product enfumafungin (1.1). The lactol of enfumafungin was reduced using triethylsilane and trifluoroacetic acid to give pyran 1.2. Treatmentwith H2SO4 in methanol resulted in cleavage of the glucose moiety to generate 1.3 in 87%
yield over 2 steps. Carboxylic acid 1.3 was converted to the corresponding benzyl ester upon treatment with benzyl bromide to give compound 1.4in an89%yield. Reaction of 1.4 with (R)
N-sulfonyl aziridine 1.5 (prepared as shown in Scheme 2) in the presence of potassium t-pentylate and the cation complexing agent 18-crown-6 provided ether 1.6 in 78% yield. Metal reduction with sodiumin liquid ammoniaconcurrently removed the N-sulfonyl benzyl groups to generate compound 1.7, which
was converted to hydrazine intermediate 1.8 with anhydrous hydrazine and BF32·OEt 28-30 in 1,2-dichloroethane (DCE). Cyclocondensation of 1.8 with acyl amidine derivative 1.9 upon heating in acetic acid then provided ibrexafungerp (1) in 66% yield.
Thepreparationof(R)-N-sulfonylaziridine1.5 isdescribedin Scheme 2. Condensation of 3,3-dimethylbutan-2-one (1.10)with (R)-p-toluenesulfinamide (1.11) gave an 84% yield of compound 1.12, which cyclized upon treatment with trimethylsulfoxonium chloride and n-butyllithium to give chiral toluenesulfinyl aziridine 1.13 in 64% yield. Oxidation of 1.13 with meta-chloroperoxybenzoic acid afforded the tosyl-pro
tected (R)-alpha-disubstituted aziridine 1.5..
(24) Lee, A. Ibrexafungerp: First approval. Drugs 2021, 81, 1445−
1450.
(25) Jallow, S.; Govender, N. P. Ibrexafungerp: A first-in-class oral
triterpenoid glucan synthase inhibitor. J. Fungi 2021, 7, 163.
(26) Lamoth, F.; Alexander, B. D. Antifungal activities of SCY-078
(MK-3118) and standard antifungal agents against clinical non
aspergillus mold isolates. Antimicrob. Agents Chemother. 2015, 59,
4308−4311

(27) Scorneaux, B.; Angulo, D.; Borroto-Esoda, K.; Ghannoum, M.;
Peel, M.; Wring, S. SCY-078 is fungicidal against Candida species in
time-kill studies. Antimicrob. Agents Chemother. 2017, 61, e01961-16.
(28) Apgar, J. M.; Wilkening, R. R.; Parker, D. L.; Meng, D.;
Wildonger, K. J.; Sperbeck, D.; Greenlee, M. L.; Balkovec, J. M.;
Flattery, A. M.; Abruzzo, G. K.; Galgoci, A. M.; Giacobbe, R. A.; Gill, C.
J.; Hsu, M.-J.; Liberator, P.; Misura, A. S.; Motyl, M.; Nielsen Kahn, J.;
Powles, M.; Racine, F.; Dragovic, J.; Fan, W.; Kirwan, R.; Lee, S.; Liu,
H.; Mamai, A.; Nelson, K.; Peel, M. Ibrexafungerp: an orally active β
1,3-glucan synthesis inhibitor. Bioorg. Med. Chem. Lett. 2021, 32,
127661.
(29) Greenlee, M. L.; Wilkening, R.; Apgar, J.; Sperbeck, D.;
Wildonger, K. J.; Meng, D.; Parker, D. L.; Pacofsky, G. J.; Heasley, B.
H.; Mamai, A.; Nelson, K. Antifungal Agents. WO 2010019204, 2010.
(30) Greenlee, M. L.; Wilkening, R.; Apgar, J.; Wildonger, K. J.; Meng,
D.; Parker, D. L. Antifungal Agents. WO 2010019203A1, 2010.
(31) Imran, M.; Khan, S. A.; Alshammari, M. K.; Alqahtani, A. M.;
Alanazi, T. A.; Kamal, M.; Jawaid, T.; Ghoneim, M. M.; Alshehri, S.;
Shakeel, F. Discovery, development, inventions and patent review of
fexinidazole: The first all-oral therapy for human African trypanoso
miasis. Pharmaceuticals 2022, 15, 128.

SYN

European Journal of Medicinal Chemistry 245 (2023) 114898

The gram-scale synthesis of this drug is demonstrated in Scheme 3 [50]. Starting with triterpene glycoside enfumafungin 14, a reduction of the bridging hemiacetal with triethylsilane provided the intermediate 15, followed by hydrolysis, etherification and benzyl protection, gave compound 16 in 76% yield over 2 steps. Subsequent ring-opening alkylation reaction of 16 with tosyl protected aziridine 17 gave com pound 18, which then underwent Borch reduction to provide the in termediate 19. Treatment of 19 with biaryl 20 in the presence of boron trifluoride diethyl etherate gave rise to the substitution product ibrexafungerp. In this synthetic method, the pyridine-triazolium biaryl and chiral benzene sulfonamide were elegantly introduced into the triterpene enfumafungin through ring-opening and substitution reactions to give the triterpene derivative. These elegant and practical synthetic
methods could be employed as the versatile tools for the synthesis of other drug molecules.

[50] J.M. Apgar, R.R. Wilkening, D.L. Parker, J.D. Meng, K.J. Wildonger, D. Sperbeck,
M.L. Greenlee, J.M. Balkovec, A.M. Flattery, G.K. Abruzzo, A.M. Galgoci, R.
A. Giacobbe, C.J. Gill, M.J. Hsu, P. Liberator, A.S. Misura, M. Motyl, J.N. Kahn,
M. Powles, F. Racine, J. Dragovic, W. Fan, R. Kirwan, S. Lee, H. Liu, A. Mamai,
K. Nelson, M. Peel, Ibrexafungerp: an orally active β-1, 3-glucan synthesis
inhibitor, Bioorg, Med. Chem. Lett. 32 (2021), 127661.

.

References

1. ^ Jump up to:^{a b c d e f g} https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214900s000lbl.pdf
2. ^ 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

1. 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]
2. 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]
3. 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]
4. 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]
5. 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]
6. 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]
7. 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]
8. 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]
9. FDA Approved Drug Products: Brexafemme (Ibrexafungerp) Oral Tablet [Link]

Clinical data
Pronunciation	/aɪˌbrɛksəˈfʌndʒɜːrp/ eye-BREKS-ə-FUN-jurp
Trade names	Brexafemme
Other names	SCY-078
License data	US DailyMed: Ibrexafungerp
Pregnancy category	Contraindicated[1]
Routes of administration	oral, intravenous
Drug class	Antifungal
ATC code	J02AX07 (WHO)
Legal status
Legal status	US: ℞-only[1]
Pharmacokinetic data
Protein binding	>99%[1]
Metabolism	Hydroxylation (CYP3A4) then conjugation (glucuronidation, sulfation)[1]
Elimination half-life	20 hours[1]
Identifiers
IUPAC name
CAS Number	1207753-03-4as citrate: 1965291-08-0
PubChem CID	46871657as citrate: 137552087
DrugBank	DB12471as citrate: DBSALT003185
UNII	A92JFM5XNUas citrate: M4NU2SDX3E
KEGG	D11544as citrate: D11545
ChEMBL	ChEMBL4297513as citrate: ChEMBL4298168
CompTox Dashboard (EPA)	DTXSID901336871
Chemical and physical data
Formula	C44H67N5O4
Molar mass	730.051 g·mol−1
3D model (JSmol)	Interactive image
SMILES
InChI

/////////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