title: Synthesis and in vitro DMPK profiling of a 1,2-dioxolane-based library with activity against Plasmodium falciparum.
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 EC(50)s30nM against Plasmodium falciparum 3D7 and Dd2 strains, and another 15 compounds had EC(50)s50nM 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, LogD 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.
authors.affiliation: Broad Institute Infectious Diseases Initiative, 7 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Derek C
authors.initials: DC
authors.lastname: Martyn
authors.forename: Galina
authors.initials: G
authors.lastname: Beletsky
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Cortese
authors.forename: Erin
authors.initials: E
authors.lastname: Tyndall
authors.forename: Hanlan
authors.initials: H
authors.lastname: Liu
authors.forename: Maria M
authors.initials: MM
authors.lastname: Fitzgerald
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: O'Shea
authors.forename: Beirong
authors.initials: B
authors.lastname: Liang
authors.forename: Jon
authors.initials: J
authors.lastname: Clardy
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004148:Dioxolanes / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects*; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D054852:Small Molecule Libraries
chemical_list: D000962:Antimalarials; D065607:Cytochrome P-450 Enzyme Inhibitors; D004148:Dioxolanes; D020033:Protein Isoforms; D054852:Small Molecule Libraries; D003577:Cytochrome P-450 Enzyme System