Triazine compounds and compositions thereof and methods for treating malaria and chemoprophylaxis
Inventors
Sciotti, Richard J. • Reichard, Gregory A. • Pannone, Kristina M. • Zottig, Victor E.
Assignees
Walter Reed Army Institute of Research
Publication Number
US-9700562-B2
Publication Date
2017-07-11
Expiration Date
2034-03-13
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Abstract
Disclosed herein are triazine compounds and methods of making and using thereof to treat malaria, provide chemoprophylaxis, and/or treat or inhibit infection by one or more Plasmodium spp.
Core Innovation
The present invention discloses novel triazine compounds and compositions thereof, as well as methods of making and using these compounds to treat malaria, provide chemoprophylaxis, and inhibit infection by one or more Plasmodium species in subjects. These compounds were designed through compound library screening and structure activity relationship (SAR) analysis using in vitro blood stage assays. A lead compound, Compound 641, demonstrated excellent in vitro potency and metabolic stability, providing complete cures in mice after a single oral dose and showing effectiveness in a primate model when dosed weekly.
The invention addresses the critical need for new antimalarial drugs due to the emergence of resistance in many structural classes of current therapies. Several strategies were employed to reduce binding affinity to the hERG potassium channel, which is associated with cardiotoxicity, by altering amine basicity, steric hindrance, and overall molecular lipophilicity, while maintaining antimalarial efficacy. Over 760 substituted triazine compounds were profiled, exhibiting good in vitro potency, little cross-resistance, and favorable pharmacokinetics, suggesting their potential as effective, low-cost malaria treatments and prophylactics.
Claims Coverage
The patent contains one independent claim directed to compounds of formula I and their pharmaceutical uses. The main inventive features are related to the specific chemical structure and its application in treating malaria and Plasmodium infections.
Novel triazine compound structures
The invention claims compounds of formula I, characterized by a triazine core with specific substitutions including aromatic rings with 0-4 heteroatoms, nitrogen-attached monocyclic or bicyclic rings as substituents, and various linkers. Restrictions include positional constraints on nitrogen atoms and substitutions on ring carbons and nitrogens.
Pharmaceutical compositions comprising the compounds
Pharmaceutical compositions that include one or more compounds of formula I combined with pharmaceutically acceptable excipients are also claimed.
Methods of treating malaria and Plasmodium infection
Methods comprising administering a therapeutically effective amount of the compounds or compositions for treating or inhibiting infection by Plasmodium species, including treatment of malaria and providing chemoprophylaxis, before, during, or after exposure to the pathogen.
Kit for administration
A kit is claimed that includes one or more doses of the compounds or pharmaceutical compositions packaged with a supplementary active ingredient and instructions for administration and use.
Overall, the claims cover specific triazine compound structures, their pharmaceutical compositions, methods of treatment for malaria and Plasmodium infections, and kits for their administration.
Stated Advantages
The compounds exhibited excellent in vitro potency against various drug resistant Plasmodium strains with IC50 values typically below 500 ng/mL, many under 150 ng/mL.
They demonstrated significant in vivo efficacy in rodent and primate malaria models, including complete cures and effective prophylaxis at relatively low doses.
Modifications to reduce binding affinity to the hERG channel reduce cardiotoxicity risk while maintaining antimalarial activity.
Compounds possess favorable pharmacokinetic properties including long half-life and good exposure, enabling convenient dosing schedules.
Synthesis is concise with 2-4 steps, suggesting practicality and cost-effectiveness.
Documented Applications
Treatment of malaria disease and infection by Plasmodium spp. in mammalian subjects including humans.
Providing chemoprophylaxis against malaria and Plasmodium infections.
Treatment or inhibition of infections by various Plasmodium strains, including drug resistant strains such as D6, W2, C235, and C2B.
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