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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Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

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View interactive charts of activity data across species
2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the CDK toolkit. All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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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
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

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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)
InChI Key VDGXZSSDCDPCRF-UHFFFAOYSA-N
No information available.
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 [2,5]. 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. 2,5
Pharmacokinetics Click here for help
Elimination
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].