Novel orally active inhibitors of β-1,3-glucan synthesis derived from enfumafungin

Apgar, James M.; Wilkening, Robert R.; Greenlee, Mark L.; Balkovec, James M.; Flattery, Amy; Abruzzo, George K.; Galgoci, Andrew; Giacobbe, Robert A.; Gill, Charles; Hsu, Ming-Jo; Liberator, Paul; Misura, Andrew S.; Motyl, Mary; Kahn, Jennifer Nielsen; Powles, M A; Racine, Fred; Dragovic, Jasminka; Habulihaz, Bahanu; Wu, Fan; Kirwan, Robin; Lee, Shu; Líu, Hao; Mamai, Ahmed; Nelson, Kingsley H.; Peel, Michael R.

doi:10.1016/j.bmcl.2015.10.011

Cited by 23 publications

(15 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Ibrexafungerp (formerly SCY-078), is an orally bioavailable, semi-synthetic modified compound of enfumafungin, a triterpene glycoside natural product (5,6). Ibrexafungerp laboratory testing showed broad activity against Candida species including fluconazole-resistant C. albicans, and C. auris (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

In vitro Efficacy of Novel Glucan Synthase Inhibitor, Ibrexafungerp (SCY-078), Against Multidrug- and Pan-resistant Candida auris Isolates from the Outbreak in New York

Zhu

Barat

Borroto–Esoda

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

Section: Introductionmentioning

confidence: 99%

In vitro Efficacy of Novel Glucan Synthase Inhibitor, Ibrexafungerp (SCY-078), Against Multidrug- and Pan-resistant Candida auris Isolates from the Outbreak in New York

Zhu

Barat

Borroto–Esoda

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Besides, the NH linker region was a typical metabolic sensitive site. 15 Hence, we first introduced a series of straight-chain, branched alkyl, and substituted alkyl groups in the linker region to investigate the tolerant region and block the potential metabolic sensitive sites (Figure 2A and 2B). Next, the best alkyl group (The methyl was determined by further biological assays) was proposed to be hopped on the central pyrimidine ring to occupy the hydropholic subpocket and simultaneously remain the water-mediated hydrogen bond (Figure 2C).…”

Section: Design Rationalementioning

confidence: 99%

Hydrophobic Pocket Occupation Design of Difluoro-Biphenyl-Diarylpyrimidines as Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors: from N-Alkylation to Methyl Hopping on the Pyrimidine Ring

et al. 2021

View full text Add to dashboard Cite

Considering the non-ideal metabolic stability of the difuloro-biphenyl-diarylpyrimidine lead compound 4, a series of novel alkylated difuloro-biphenyl-diarylpyrimidines were structure-based designed and synthesized as non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs). Introducing alkyl or substituted alkyl groups on the linker region (consist of V179, Y181, E138 residues) to block the potential metabolic sensitive sites obtained twenty-two derviatives. Among them, compound 12a with N-methyl group displayed excellent HIV-1 inhibitory activity (EC 50 = 6.16 nM), moreover, a significant improvement in the selectivity (SI = 24,069) compared with existing drugs (NVP, SI > 72; ETR, SI > 1159; EFV, SI > 1600). Finally, the methyl group was hopped to the central pyrimidine ring in order to occupy the small linker region and maintain the water-mediated hydrogen bond observed in the binding of compound 4 with RT. The resulting compound 16y exhibited an improved HIV-1 inhibitory activity (EC 50 = 1.37 nM) and much lower cytotoxicity with the SI > 208,333). In addition, compound 16y possessed nanomolar activity toward multiple single-mutant virus strains except Y188L. For the metabolic stability, compound 16y have a better stability in human liver microsomes (T 1/2 = 138 min, Cl int = 5.0 μL/min/mg) than compounds 4 (T 1/2 = 44 min, Cl int = 16 μL/min/mg). No apparent in vivo acute toxicity was observed in 16y-treated female, and especially pregnant mice. The molecular docking studies predicted the binding modes of 16y with RT, and the methyl group was displayed as occupying effect in the hydrophobic pocket, explaining the activity differences for 16y and the precursor 12a. This series of alkylated compounds with highly potency and safety represent promising lead template for future discovery.

show abstract

“…86 SCY-078 (Synexis Inc, Jersey City, NJ, USA), an enfumafungin derivative inhibits glucan synthase and although structurally not an echinocandin, belonging to the triterpene drug class, inhibits (1-3) β-D-glucan. 87 It is active against Candida spp. including C. auris and FKS mutants, and has good activity against Aspergillus, including azole resistant isolates.…”

Section: Agents Targeting Fungal Metabolic Pathwaysmentioning

confidence: 99%

Diagnosis and treatment of invasive fungal infections: looking ahead

Sanguinetti

Posteraro

Beigelman-Aubry³

et al. 2019

Journal of Antimicrobial Chemotherapy

View full text Add to dashboard Cite

Improved standards of care depend on the development of new laboratory diagnostic and imaging procedures and the development of new antifungal compounds. Immunochromatography technologies have led to the development of lateral flow devices for the diagnosis of cryptococcal meningitis and invasive aspergillosis. Similar devices are being developed for the detection of histoplasmosis, which meet the requirements for speed (~15 min assay time) and ease of use for point-of-care (POC) diagnostics. The evolution of molecular tools for the detection of fungal pathogens has been slow but the introduction of new nucleic acid amplification techniques appears to be helpful, for example T2Candida. An Aspergillus proximity ligation assay has been developed for a rapid near-patient bedside diagnosis of invasive aspergillosis. Computed tomography (CT) remains the cornerstone for radiological diagnosis of invasive pulmonary fungal infections. Magnetic resonance imaging (MRI) of the lungs may be performed to avoid radiation exposure. MRI with T2-weighted turbo-spin-echo sequences exhibits sensitivity and specificity approaching that of CT for the diagnosis of invasive pulmonary aspergillosis. The final part of this review looks at new approaches to drug discovery that have yielded new classes with novel mechanisms of action. There are currently two new classes of antifungal drugs in phase 2 study for systemic invasive fungal disease and one in phase 1. These new antifungal drugs show promise in meeting unmet needs with oral and intravenous formulations available and some with decreased potential for drug-drug interactions. Novel mechanisms of action mean these agents are not susceptible to the common resistance mechanisms seen in Candida or Aspergillus.Modification of existing antifungal susceptibility techniques may be required to incorporate these new compounds.

show abstract

Novel orally active inhibitors of β-1,3-glucan synthesis derived from enfumafungin

Cited by 23 publications

References 23 publications

In vitro Efficacy of Novel Glucan Synthase Inhibitor, Ibrexafungerp (SCY-078), Against Multidrug- and Pan-resistant Candida auris Isolates from the Outbreak in New York

In vitro Efficacy of Novel Glucan Synthase Inhibitor, Ibrexafungerp (SCY-078), Against Multidrug- and Pan-resistant Candida auris Isolates from the Outbreak in New York

Hydrophobic Pocket Occupation Design of Difluoro-Biphenyl-Diarylpyrimidines as Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors: from N-Alkylation to Methyl Hopping on the Pyrimidine Ring

Diagnosis and treatment of invasive fungal infections: looking ahead

Contact Info

Product

Resources

About