Synthesis and biological evaluation of antifungal derivatives of enfumafungin as orally bioavailable inhibitors of β-1,3-glucan synthase

Heasley, Brian; Pacofsky, Gregory J.; Mamai, Ahmed; Líu, Hao; Nelson, Kingsley H.; Coti, Ghjuvanni; Peel, Michael R.; Balkovec, James M.; Greenlee, Mark L.; Liberator, Paul; Meng, Dongfang; Parker, Dann L.; Wilkening, Robert R.; Apgar, James M.; Racine, Fred; Hsu, Ming-Jo; Giacobbe, Robert A.; Kahn, Jennifer Nielsen

doi:10.1016/j.bmcl.2012.05.031

Cited by 29 publications

(16 citation statements)

References 15 publications

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“…Enfumafungin was identified as having antifungal activity during a natural product screening campaign (11), and SCY-078 was selected for development following a lead optimization program to improve potency, breadth of activity, and drug-like properties including oral bioavailability (12–14). It is well established that oral bioavailability reflects contributions from multiple processes, including solubility at physiologically relevant pHs in the stomach and intestinal lumen, absorptive permeability, and first-pass metabolism.…”

Section: Discussionmentioning

confidence: 99%

Preclinical Pharmacokinetics and Pharmacodynamic Target of SCY-078, a First-in-Class Orally Active Antifungal Glucan Synthesis Inhibitor, in Murine Models of Disseminated Candidiasis

Wring

Randolph

Park

et al. 2017

Antimicrob Agents Chemother

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SCY-078 (MK-3118) is a novel, semisynthetic derivative of enfumafungin and represents the first compound of the triterpene class of antifungals. SCY-078 exhibits potent inhibition of β-(1,3)-d-glucan synthesis, an essential cell wall component of many pathogenic fungi, including Candida spp. and Aspergillus spp. SCY-078 is currently in phase 2 clinical development for the treatment of invasive fungal diseases. In vitro disposition studies to assess solubility, intestinal permeability, and metabolic stability were predictive of good oral bioavailability. Preclinical pharmacokinetic studies were consistent with once-daily administration to humans. After intravenous delivery, plasma clearance in rodents and dogs was low, representing <15% and <25% of hepatic blood flow, respectively. The terminal elimination-phase half-life was 5.5 to 8.7 h in rodents, and it was ∼9.3 h in dogs. The volume of distribution at steady-state was high (4.7 to 5.3 liters/kg), a finding suggestive of extensive tissue distribution. Exposure of SCY-078 in kidney tissue, a target organ for invasive fungal disease such as candidiasis, exceeded plasma by 20- to 25-fold for the area under the concentration-time curve from 0 h to infinity (AUC0–∞) and Cmax. SCY-078 achieved efficacy endpoints following oral delivery across multiple murine models of disseminated candidiasis. The pharmacokinetic/pharmacodynamic indices Cmax/MIC and AUC/MIC correlated with outcome. Target therapeutic exposure, expressed as the plasma AUC0–24, was comparable across models, with an upper value of 11.2 μg·h/ml (15.4 μM·h); the corresponding mean value for free drug AUC/MIC was ∼0.75. Overall, these results demonstrate that SCY-078 has the oral and intravenous (i.v.) pharmacokinetic properties and potency in murine infection models of disseminated candidiasis to support further investigation as a novel i.v. and oral treatment for invasive fungal diseases.

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Section: Discussionmentioning

confidence: 99%

Preclinical Pharmacokinetics and Pharmacodynamic Target of SCY-078, a First-in-Class Orally Active Antifungal Glucan Synthesis Inhibitor, in Murine Models of Disseminated Candidiasis

Wring

Randolph

Park

et al. 2017

Antimicrob Agents Chemother

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“…The compound, named enfumafungin, is a new triterpene glycoside that inhibits the (1,3)- β -D-glucan synthase. Several synthetic products derived from enfumafungin are currently under development in order to optimize in vivo antifungal activity and oral efficacy [57]. …”

Section: Need Of New Antifungal Agentsmentioning

confidence: 99%

CandidaInfections, Causes, Targets, and Resistance Mechanisms: Traditional and Alternative Antifungal Agents

Spampinato

Leonardi

2013

BioMed Research International

308

261

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The genus Candida includes about 200 different species, but only a few species are human opportunistic pathogens and cause infections when the host becomes debilitated or immunocompromised. Candida infections can be superficial or invasive. Superficial infections often affect the skin or mucous membranes and can be treated successfully with topical antifungal drugs. However, invasive fungal infections are often life-threatening, probably due to inefficient diagnostic methods and inappropriate initial antifungal therapies. Here, we briefly review our current knowledge of pathogenic species of the genus Candida and yeast infection causes and then focus on current antifungal drugs and resistance mechanisms. An overview of new therapeutic alternatives for the treatment of Candida infections is also provided.

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“…Besides having a narrow spectrum, echinocandins have to be administered intravenously as a result of poor oral bioavailability [57]. However, an orally bioavailable analog (enfumafungin) is currently under development [59].…”

Section: Current Antifungal Agents and Their Limitationsmentioning

confidence: 99%

In pursuit of the ideal antifungal agent for Candida infections: high-throughput screening of small molecules

Wong

Samaranayake

Seneviratne

2014

Drug Discovery Today

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Synthesis and biological evaluation of antifungal derivatives of enfumafungin as orally bioavailable inhibitors of β-1,3-glucan synthase

Cited by 29 publications

References 15 publications

Preclinical Pharmacokinetics and Pharmacodynamic Target of SCY-078, a First-in-Class Orally Active Antifungal Glucan Synthesis Inhibitor, in Murine Models of Disseminated Candidiasis

Preclinical Pharmacokinetics and Pharmacodynamic Target of SCY-078, a First-in-Class Orally Active Antifungal Glucan Synthesis Inhibitor, in Murine Models of Disseminated Candidiasis

CandidaInfections, Causes, Targets, and Resistance Mechanisms: Traditional and Alternative Antifungal Agents

In pursuit of the ideal antifungal agent for Candida infections: high-throughput screening of small molecules

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