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: Suman K Vodnala, Thomas Lundbäck, Birger Sjöberg, Richard Svensson, Martin E Rottenberg, Lars G J Hammarström
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 57 Issue 2 Pg. 1012-8 (Feb 2013) ISSN: 1098-6596 [Electronic] United States
• PMID: 23254423 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 6-((6-fluoro-3,4-dihydro-2H-1-benzopyran-4-yl))oxy-N-(piperidin-4-yl)pyrazin-2-amine
• Aminopyridines
• Benzopyrans
• Piperidines
• Pyrazines
• Trypanocidal Agents
• 2-aminopyrazine
• alpha-aminopyridine

Topics

• Aminopyridines (pharmacology, therapeutic use)
• Animals
• Benzopyrans (pharmacology, therapeutic use)
• Cell Line
• Humans
• Mice
• Mice, Inbred C57BL
• Piperidines (pharmacology, therapeutic use)
• Pyrazines (pharmacology, therapeutic use)
• Trypanocidal Agents (pharmacology, therapeutic use)
• Trypanosoma brucei brucei (drug effects)
• Trypanosoma brucei gambiense (drug effects)
• Trypanosoma brucei rhodesiense (drug effects)
• Trypanosomiasis, African (drug therapy, parasitology)