Novel Benzyl-Piperidine antifungal agents to treat intractable Mucorales infections

Title: Novel Benzyl-Piperidine antifungal agents to treat intractable Mucorales infections ABSTRACT. The fungal order Mucorales [a WHO “High Priority Group” fungal pathogen] are the causative agents of mucormycosis, an aggressive, opportunistic mould infection that has devasting outcomes, with an overall mortality rate of ~50-60%. Mucormycosis primarily afflicts immunosuppressed patients. The progression of the disease is rapid. Once the infection has disseminated, it is almost always fatal. Treatment options for mucormycosis are severely limited, as these fungi are intrinsically resistant to contemporary antifungals, including the echinocandins and most of the azoles. The antifungal agents in the development pipeline exhibit poor or no activity against Mucorales, making the development of new, potent, and safe antifungals against Mucorales remains an urgent, unmet need. To address this need, we identified a novel series of Benzyl-Piperidines (BPs) that exhibit potent antifungal activity against pathogenic moulds. A representative BP, MBX-7591, exhibited potent antifungal activity against representative pathogens of the Mucorales, such as Rhizopus delemar and Mucor lusitanicus, in in vitro susceptibility assays and in a murine model of acute invasive pulmonary mucormycosis. Based on these exciting results, we propose to develop the BP series into a promising new generation of safe and in vivo efficacious small molecules to combat the growing emergence of drug-resistant human fungal infections. The goal of this Phase 1 STTR application is to chemically optimize the BP series to improve drug-like properties and antifungal activity against Mucorales using an SAR-driven approach. In Aim 1, we will chemically optimize the drug-like properties and antifungal activity of the BP lead series vs. Mucor species using an SAR- driven medicinal chemistry approach. Novel analogs will be evaluated in an assay funnel and prioritized based on in vitro potency, cytotoxicity, in vitro ADME and toxicology assays in Aim 2. SAR data will be used in the design of new analogs in an iterative process that will result in 2-3 analogs that will meet the criteria for Lead Compound designation. Analogs that meet the cumulative milestones of Aims 1 and 2 will be evaluated in in vivo assays for tolerability, pharmacokinetics, and efficacy in a murine model of invasive pulmonary mucormycosis in Aim 3. An analog that meets the cumulative milestone criteria for Aims 1-3 will be designated as a Lead Compound that will be optimized further in a follow-on Phase 2 project, resulting in a Preclinical Candidate that is ready for IND-enabling preclinical development. Taken together, the proposed studies will further develop an exciting series of novel small molecules with the potential to meet an unmet medical need posed by clinically challenging, pathogenic moulds.