Synthesis and in vitro DMPK profiling of a 1,2-dioxolane-based library with activity against Plasmodium falciparum |
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| Authors: | Derek C Martyn Galina Beletsky Joseph F Cortese Erin Tyndall Hanlan Liu Maria M Fitzgerald Thomas J O’Shea Beirong Liang Jon Clardy |
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| Institution: | 1. Broad Institute Infectious Diseases Initiative, 7 Cambridge Center, Cambridge, MA 02142, USA;2. Chemical Biology Platform, 7 Cambridge Center, Cambridge, MA 02142, USA;3. Drug and Biomaterial R&D, Genzyme Corporation, Waltham, MA 02451, USA;4. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA |
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| Abstract: | A 43-member 1,2-dioxolane library was synthesized by coupling a 1,2-dioxolane-3-acetic acid derivative to a range of amines. Ten compounds had EC50s ? 30 nM against Plasmodium falciparum 3D7 and Dd2 strains, and another 15 compounds had EC50s ? 50 nM against both 3D7 and Dd2. The library was then subjected to a range of in vitro DMPK assays, which revealed that side chains with a heteroatom were required for favorable solubility, Log D and membrane permeability. CYP450 inhibition was isoform dependent, with 2C19 and 3A4 particularly susceptible, and the majority of compounds tested against rat and human microsomes were metabolized rapidly. |
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