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.
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2D Structure
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Physico-chemical Properties
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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
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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
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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]). Recruitment has commenced for a Phase 2 trial for combination therapy with lumefantrine (NCT03167242, last update March, 2021).
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
Ganaplacide has a mean terminal half-life for elimination of 44.1 hours [5].