P218   Click here for help

GtoPdb Ligand ID: 9740

Synonyms: MMV000147
PDB Ligand Antimalarial Ligand
Compound class: Synthetic organic
Comment: The antifolate compound P218 is a potent and selective inhibitor of P. falciparum bifunctional dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) and was designed to overcome the emergence of parasite resistance to this class of antimalarial compound [7].

The Malaria tab on this ligand page provides additional curator comments of relevance to the Guide to MALARIA PHARMACOLOGY.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 6
Hydrogen bond donors 3
Rotatable bonds 10
Topological polar surface area 133.58
Molecular weight 360.18
XLogP 1.72
No. Lipinski's rules broken 0
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Canonical SMILES CCc1nc(N)nc(c1OCCCOc1ccccc1CCC(=O)O)N
Isomeric SMILES CCc1nc(N)nc(c1OCCCOc1ccccc1CCC(=O)O)N
InChI InChI=1S/C18H24N4O4/c1-2-13-16(17(19)22-18(20)21-13)26-11-5-10-25-14-7-4-3-6-12(14)8-9-15(23)24/h3-4,6-7H,2,5,8-11H2,1H3,(H,23,24)(H4,19,20,21,22)
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Summary of Clinical Use Click here for help
P218 has entered Phase 1 clinical trial for malaria. A first-in-human study to confirm the safety, tolerability and pharmacokinetics of P218 in healthy adult subjects (NCT02885506) has been completed and results published [2,6]. A Phase 1b trial, to evaluate the safety, tolerability and chemoprotective activity of P218 in a P. falciparum sporozoite infection model has also been completed and results posted with ClinicalTrials.gov (NCT03707041) [1].
Mechanism Of Action and Pharmacodynamic Effects Click here for help
P218 is a selective inhibitor of P. falciparum bifunctional dihydrofolate reductase-thymidylate synthase (PfDHFR-TS), binding to the active site of DHFR differently than to the human enzyme [7]. In contrast to pyrimethamine, P218 employs a a slow-on/slow-off tight-binding mode as well as binding both wild-type and pyrimethamine-resistant quadruple mutant PfDHFR, which could prolong the the target residence time [7].
Clinical Trials
Clinical Trial ID Title Type Source Comment References
NCT03707041 Safety, Tolerability and Chemoprotective Activity of P218 in PfSPZ Challenge Model Phase 1 Interventional Medicines for Malaria Venture 1
NCT02885506 A FIH Study to Investigate the Safety, Tolerability and PK of P218 Phase 1 Interventional Medicines for Malaria Venture Favourable safety, tolerability and pharmacokinetics displayed. The short half-life will reqiure a long‐acting formulation. 2,6
Pharmacokinetics Click here for help
P218 has a half-life ranging from 3.1 to 6.7 hours (doses of 10 and 30 mg) increasing to 19.6 hours with higher doses (up to 1000 mg) [2].