Cipargamin
chemical compound
Cipargamin (also known as KAE609 or NITD609) is a synthetic antimalarial compound belonging to the novel spiroindolone drug class. Developed by Novartis Institute for Tropical Diseases in Singapore, through a collaboration with the Genomics Institute of the Novartis Research Foundation (GNF), the Biomedical Primate Research Centre and the Swiss Tropical Institute, cipargamin represents a promising next-generation antimalarial drug currently undergoing Phase II clinical trials with a particular focus on safety evaluation. Cipargamin was awarded MMV Project of the Year 2009.
Mechanism of action
Cipargamin exerts its antimalarial activity by targeting PfATP4, a P-type Na+ ATPase located on the plasma membrane of Plasmodium parasites. By inhibiting this essential sodium pump, cipargamin disrupts the sodium homeostasis within the parasite, leading to cell swelling and ultimately parasite death. This mechanism of action distinguishes cipargamin from existing antimalarial drugs, including artemisinin derivatives and other peroxide-based compounds.
Structure-activity relationships
The spiroindolone structure of cipargamin features a complex stereochemical configuration that is critical for its antimalarial activity. Structure-activity relationship studies have demonstrated that the (1R,3S) stereochemical configuration is essential for optimal antimalarial potency. It is structurally related to GNF 493, a compound first identified as a potent inhibitor of Plasmodium falciparum growth in a high throughput phenotypic screen of natural products conducted at the Genomics Institute of the Novartis Research Foundation in San Diego, California in 2006.
Clinical development
Phase I studies
Initial Phase I clinical trials evaluated the safety, tolerability, and pharmacokinetics of cipargamin in healthy volunteers and patients with uncomplicated P. falciparum malaria.
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