Background: Glucan synthase (GS) inhibitors suitable for oral administration are an unmet medical need. Methods & Results: We discovered N-[2-(3,4-dihydro-1H-2-benzopyran-1-yl)-ethyl]-N-methyl-1-phenyl-4-piperidinamine as a small molecular weight inhibitor of GS. Chemistry on this template yielded noncompetitive inhibitors of GS in microsomal membranes from Candida albicans, Aspergillus fumigatus and Candida krusei. Favorable compounds were specific for GS with little inhibitory activity against chitin synthase, trehalose-6-phosphate synthase or plasma membrane H+-ATPase. GS inhibitors did not block cellular DNA, RNA or protein synthesis in Saccharomyces cerevisiae, but did block glucan synthesis in C. albicans cultures. Representative compounds altered the expression of genes with roles in maintaining cell envelope integrity as shown by microarray analyses of S. cerevisiae cultures. Fungal pathogens including C. albicans (n=2), C. glabrata, C. krusei, C. parapsilosis, A. fumigatus (n=2) and A. terreus were used for MIC determinations (NCCLS method). The compound named above inhibited only C. krusei with MIC values ranging from 16-128 μg/ml. A bromine-substituted analog inhibited all eight fungi with MIC values ranging from 0.25 to 32 μg/ml, depending on the species. GS inhibitors were cidal against C. albicans, C. krusei and A. fumigatus. Optimal compounds inhibited the growth of rat hepatoma cell cultures less than amphotericin B or ketoconazole. GS inhibitors had good monolayer permeability in the Caco-2 human colon adenocarcinoma cellular model of intestinal transport, consistent with oral bioavailabilities in the mouse of 25-80%. Conclusion: We elaborated a novel class of GS inhibitors achieving target specificity, activity against multiple fungal pathogens, moderate potency, and satisfactory pharmaceutics properties.
Full conference title:
- ICAAC 42nd