Discovery of Plant Sterol-Derived Gamma-Secretase Modulators by Molecular Editing of a Triterpenoid Glycoside


While natural products have been refined through cycles of selection/diversification, they are often suboptimal as orally bioavailable pharmacological agents and, thus, 'editing' particular metabolic or chemical 'soft spots' within a naturally occurring molecular structure can be beneficial to its development as a drug candidate. For example, the complex molecular framework of the antifungal triterpenoid glycoside, enfumafungin, was modified in the course of medicinal chemistry studies to excise undesirable functionality such as a cyclic hemiacetal and C3-O monosaccharide moiety, both of which were found to be either chemically or enzymatically labile. These research efforts culminated in the development of the antifungal clinical candidate SCY-078, the first orally active glucan synthase inhibitor.

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Sunday, October 27, 2013
New antifungal drugs