MK-5204: An orally active β-1,3-glucan synthesis inhibitor

Area of Science:

• Medicinal Chemistry
• Mycology
• Pharmacology

Background:

• Enfumafungin is a β-1,3-glucan synthesis inhibitor with potential for oral activity.
• Previous semi-synthetic modifications focused on C2 and C3 positions to enhance oral bioavailability.
• Further optimization is needed to improve efficacy and reduce liabilities like N-dealkylation.

Purpose of the Study:

• To further optimize the C2 heterocyclic substituent of enfumafungin derivatives.
• To identify novel orally active β-1,3-glucan synthesis inhibitors.
• To develop a compound with broad-spectrum antifungal activity and improved pharmacokinetic properties.

Main Methods:

• Semi-synthetic modification of enfumafungin derivatives.
• Exploration of alternative C2 heterocyclic substituents, including 3-carboxamide-1,2,4-triazole.
• Modification of the C3 glycoside moiety and the alpha amino substituent.
• Evaluation of antifungal activity against Candida species.
• Assessment of oral efficacy in a murine model of disseminated Candidiasis.

Main Results:

• 3-carboxamide-1,2,4-triazole demonstrated comparable antifungal activity to aminotetrazole at the C2 position.
• Alkylation at C2 or C3 did not significantly improve oral efficacy.
• Replacement of the isopropyl alpha amino substituent with tert-butyl improved oral exposure.
• The resulting compound, MK-5204, exhibited broad-spectrum activity against Candida species.
• MK-5204 showed robust oral efficacy in a murine model and lacked the N-dealkylation liability of prior leads.

Conclusions:

• MK-5204 represents a significant advancement in the development of orally active antifungal agents.
• The structural modifications, particularly the C2 substituent and tert-butyl group, are crucial for improved oral efficacy and reduced liabilities.
• MK-5204 demonstrates potential as a novel therapeutic agent for invasive candidiasis.