cipargamin   Click here for help

GtoPdb Ligand ID: 9721

Synonyms: KAE609 | NITD609
Antimalarial Ligand
Compound class: Synthetic organic
Comment: Cipargamin is an antimalarial drug candidate, under clinical development. It is the optimised lead for the spiroindolones, a novel class of compounds identified from a phenotypic screen as having antimalarial activity [3,9] and awarded MMV Project of the Year (2009).
The active enantiomer is shown here, with the 1R,3S configuration essential for antimalarial activity [3].

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 3
Hydrogen bond donors 3
Rotatable bonds 0
Topological polar surface area 56.92
Molecular weight 389.05
XLogP 4.62
No. Lipinski's rules broken 0
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Canonical SMILES CC1Cc2c3cc(F)c(cc3[nH]c2C2(N1)C(=O)Nc1c2cc(Cl)cc1)Cl
Isomeric SMILES C[C@H]1Cc2c3cc(F)c(cc3[nH]c2[C@@]2(N1)C(=O)Nc1c2cc(Cl)cc1)Cl
InChI InChI=1S/C19H14Cl2FN3O/c1-8-4-11-10-6-14(22)13(21)7-16(10)23-17(11)19(25-8)12-5-9(20)2-3-15(12)24-18(19)26/h2-3,5-8,23,25H,4H2,1H3,(H,24,26)/t8-,19+/m0/s1
No information available.
Summary of Clinical Use Click here for help
Cipargamin is in clinical development with completion of several Phase 2 clinical trials (NCT01836458, NCT01524341, NCT01860989, NCT03334747) to assess safety and efficacy in patients with uncomplicated P. falciparum or P. vivax malaria.
Evaluation of piperaquine as a potential combination therapy partner indicates no significant effect on exposure to either compound and no safety concerns [6].
Mechanism Of Action and Pharmacodynamic Effects Click here for help
The exact mechanism of action of cipargamin is not fully understood but Plasmodium non-SERCA-type Ca2+-transporting P-ATPase (PfATP4) may be a possible target because mutatations in PfATP4 confer resistance to this compound [3]. PfATP4 is thought to regulate Na+ homeostasis and play a role in maintaining the low cytosolic Na+ concentration essential for the Plasmodium parasite to survive during the intraerythrocytic stages of development [5].
Clinical Trials
Clinical Trial ID Title Type Source Comment References
NCT01860989 A Study to Assess Efficacy, Safety of KAE609 in Adult Patients With Acute Malaria Mono-infection Phase 2 Interventional Novartis
NCT01836458 A Study to Find the Minimum Inhibitory Concentration of KAE609 in Adult Male Patients With P. Falciparum Monoinfection Phase 2 Interventional Novartis 2
NCT03334747 Safety of KAE609 in Adults With Uncomplicated Plasmodium Falciparum Malaria. Phase 2 Interventional Novartis 4
NCT04675931 To Evaluate Efficacy, Safety, Tolerability and PK of Intravenous Cipargamin in Participants With Severe Plasmodium Falciparum Malaria Phase 2 Interventional Novartis Not yet recruiting (last updated March 2021).
NCT01524341 Efficacy, Safety, Tolerability and Pharmacokinetics of KAE609 in Adult Patients With Acute, Uncomplicated Plasmodium Falciparum or Vivax Malaria Mono-infection Phase 2 Interventional Novartis Rapid parasitemia clearance reported in adults with uncomplicated P. falciparum or P. vivax malaria. 8
Pharmacokinetics Click here for help
Cipargamin has a mean terminal half-life for elimination of 20.8 hours (range of 11.3 to 37.6 hours), supporting a once-daily oral dosing regimen [8].