title: In vitro and in vivo activities of 2-aminopyrazines and 2-aminopyridines in experimental models of human African trypanosomiasis.
abstract: New drugs for the treatment of human African trypanosomiasis are urgently needed. A number of 2-aminopyrazines/2-aminopyridines were identified as promising leads following a focused screen of 5,500 compounds for Trypanosoma brucei subsp. brucei viability. Described compounds are trypanotoxic in the submicromolar range and show comparably low cytotoxicity on representative mammalian cell lines. Specifically, 6-([6-fluoro-3,4-dihydro-2H-1-benzopyran-4-yl)]oxy)-N-(piperidin-4-yl)pyrazin-2-amine (CBK201352) is trypanotoxic for T. brucei subsp. brucei, T. brucei subsp. gambiense, and T. brucei subsp. rhodesiense and is nontoxic to mammalian cell lines, and in vitro preclinical assays predict promising pharmacokinetic parameters. Mice inoculated intraperitoneally (i.p.) with 25 mg/kg CBK201352 twice daily for 10 days, starting on the day of infection with T. brucei subsp. brucei, show complete clearance of parasites for more than 90 days. Thus, CBK201352 and related analogs are promising leads for the development of novel treatments for human African trypanosomiasis.
authors.affiliation: Department of Microbiology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Suman K
authors.initials: SK
authors.lastname: Vodnala
authors.forename: Thomas
authors.initials: T
authors.lastname: Lundbäck
authors.forename: Birger
authors.initials: B
authors.lastname: Sjöberg
authors.forename: Richard
authors.initials: R
authors.lastname: Svensson
authors.forename: Martin E
authors.initials: ME
authors.lastname: Rottenberg
authors.forename: Lars G J
authors.initials: LG
authors.lastname: Hammarström
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D011719:Pyrazines / Q000494:pharmacology* / Q000627:therapeutic use; D014344:Trypanocidal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D014346:Trypanosoma brucei brucei / Q000187:drug effects; D014347:Trypanosoma brucei gambiense / Q000187:drug effects; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects; D014353:Trypanosomiasis, African / Q000188:drug therapy* / Q000469:parasitology
chemical_list: C582394:6-((6-fluoro-3,4-dihydro-2H-1-benzopyran-4-yl))oxy-N-(piperidin-4-yl)pyrazin-2-amine; D000631:Aminopyridines; D001578:Benzopyrans; D010880:Piperidines; D011719:Pyrazines; D014344:Trypanocidal Agents; C079424:2-aminopyrazine; C032439:alpha-aminopyridine