Ibrexafungerp

Description

SCY-078 (Ibrexafungerp) is an oral and intravenous antifungal drug.

Uses

Ibrexafungerp (MK 3118) is an orally active β-1,3-glucan synthesis inhibitor, with potential antifungal activity. Ibrexafungerp can be used for research of Candida and Aspergillus infections[1].

Indications

Ibrexafungerp is approved for the treatment of vaginal candidiasis (VVC) in adults and children women who have experienced their first menstrual period.

Mechanism of action

Ibrexafungerp works by binding to the enzyme glucan synthase (FKS1/FKS2 complex) on the fungal cell membrane, effectively inhibiting the synthesis of β-1,3-D-glucan, which in turn disrupts the integrity of the cell wall. Since glucan is a key component in maintaining the strength of the fungal cell wall, the blockage of its synthesis leads to cell wall disintegration and death of the fungus due to osmotic pressure imbalance, thus treating those fungal infections that are resistant to conventional antifungal drugs such as azoles or echinocandins.

Synthesis

Ibrexafungerp was synthesised through a series of chemical reactions using Enfumafungin (1.1) as a starting material. The specific synthetic route is as follows:
First the lactone of Enfumafungin was reduced using triethylsilane and trifluoroacetic acid to yield the pyran compound 1.2. Subsequent treatment with sulphuric acid in methanol hydrolysed the glucose moiety to give compound 1.3, the overall yield of this two step reaction was 87%. The carboxylic acid portion of compound 1.3 was converted into the corresponding benzyl ester in the presence of benzyl bromide to yield compound 1.4 in 89% yield. The reaction of 1.4 with (R)-N-sulfonylazepane 1.5 in the presence of potassium tertiary amylate and chelating agent 18-crown-6 afforded ether 1.6 in 78% yield. Subsequent metal reduction using sodium in liquid ammonia with simultaneous removal of the N-sulfobenzyl group yielded compound 1.7.Treatment of 1.7 with anhydrous hydrazine and BF3-OEt2 in 1,2-dichloroethane (DCE) converted into the hydrazine intermediate 1.8.The cyclocondensation reaction of 1.8 with amide derivative 1.9 in heated acetic acid resulted in the synthesis of Ibrexafungerp (1 ) in 66% yield.

in vivo

References

[1] James M Apgar, et al. Ibrexafungerp: An orally active β-1,3-glucan synthesis inhibitor. Bioorg Med Chem Lett. 2021 Jan 15;32:127661. DOI:10.1016/j.bmcl.2020.127661
[2] Mahmoud Ghannoum, et al. Ibrexafungerp: A Novel Oral Triterpenoid Antifungal in Development for the Treatment of Candida auris Infections. Antibiotics (Basel). 2020 Aug 25;9(9):539. DOI:10.3390/antibiotics9090539
[3] Stephen A Wring, et al. 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):e02068-16. DOI:10.1128/AAC.02068-16
[4] Ghannoum M, et al. Efficacy of Ibrexafungerp (SCY-078) against Candida auris in an In Vivo Guinea Pig Cutaneous Infection Model. Antimicrob Agents Chemother. 2020 Sep 21;64(10):e00854-20. DOI:10.1128/AAC.00854-20
[5] Arendrup MC, et al. In Vitro Activity of Ibrexafungerp (SCY-078) against Candida auris Isolates as Determined by EUCAST Methodology and Comparison with Activity against C. albicans and C. glabrata and with the Activities of Six Comparator Agents. Antimicrob Agents Chemother. 2020 Feb 21;64(3):e02136-19. DOI:10.1128/AAC.02136-19