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ganaplacide   Click here for help

GtoPdb Ligand ID: 9946

Synonyms: GNF156 | KAF156
Antimalarial Ligand
Compound class: Synthetic organic
Comment: Ganaplacide is the optimised lead for the imidazolopiperazines (IZPs), a novel class of compounds identified from a phenotypic screen as having antimalarial activity [1].

The Malaria tab on this ligand page provides additional curator comments of relevance to the Guide to MALARIA PHARMACOLOGY.
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 Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/). 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 5
Hydrogen bond donors 2
Rotatable bonds 5
Topological polar surface area 76.18
Molecular weight 411.19
XLogP 4.09
No. Lipinski's rules broken 0

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
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.

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)

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Canonical SMILES NCC(=O)N1CCn2c(C1(C)C)nc(c2Nc1ccc(cc1)F)c1ccc(cc1)F
Isomeric SMILES NCC(=O)N1CCn2c(C1(C)C)nc(c2Nc1ccc(cc1)F)c1ccc(cc1)F
InChI InChI=1S/C22H23F2N5O/c1-22(2)21-27-19(14-3-5-15(23)6-4-14)20(26-17-9-7-16(24)8-10-17)28(21)11-12-29(22)18(30)13-25/h3-10,26H,11-13,25H2,1-2H3
InChI Key BUPRVECGWBHCQV-UHFFFAOYSA-N

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
No information available.
Summary of Clinical Use Click here for help
Clinical evaluation of ganaplacide indicates promising activity against uncomplicated P. vivax or P. falciparum infections in adult malaria patients (results from Phase 2b trial NCT01753323 published in [5]). A combination therapy (known as KLU156) that includes ganaplacide and lumefantrine was progressed to phase 3 evaluation in NCT05842954.
Mechanism Of Action and Pharmacodynamic Effects Click here for help
Decreased susceptibility to ganaplacide is associated with mutations in three P. falciparum genes, PfCARL (cyclic amine resistance locus), PfUGT (UDP-galactose) and PfACT (Acetyl-CoA transporter), but it is thought that these are involved in broad mechanisms of antimalarial drug resistance and are not considered to be likely targets of the imidazolopiperazines (IZPs) [2,4]. Further investigation has revealed that IZPs may target the Plasmodium intracellular secretory pathway, blocking parasite development by inhibiting protein trafficking, blocking the establishment of new permeation pathways and causing expansion of the endoplasmic reticulum [3].
Clinical Trials
Clinical Trial ID Title Type Source Comment References
NCT03167242 Efficacy and Safety of KAF156 in Combination With LUM-SDF in Adults and Children With Uncomplicated Plasmodium Falciparum Malaria Phase 2 Interventional Novartis
NCT01753323 Efficacy, Safety, Tolerability and Pharmacokinetics of KAF156 in Adult Patients With Acute, Uncomplicated Plasmodium Falciparum or Vivax Malaria Mono-infection Phase 2 Interventional Novartis 5
Pharmacokinetics Click here for help
Elimination
Ganaplacide has a mean terminal half-life for elimination of 44.1 hours [5].