Rationale and discovery of Pneumocandins, the lead for Caspofungin

When the antifungal screening program at Merck that led to Caspofungin was initiated, two classes of antifungal therapies were being used clinically. The first was Amphotericin B a fungicidal target which involved cell-membrane perturbation, not surprisingly, with significant toxic liabilities. The second class consisted of a variety of econozoles which inhibited ergosterol synthesis, an effective fungistatic target with, however, potential for resistance development. The goal of the screening program was to discover a fungicidal natural product as a lead for a medicinal chemistry program, which was significantly less toxic than Amphotericin B and less prone to resistance development than the econazoles. The fungal cell wall became the target and the glucan synthesis inhibitor, pneumocandin B₀ the lead that was chosen, but not without some trepidation about the challenges that had to be overcome to produce this complex natural product...