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Cipargamin: Biocatalysis in the Discovery and Development of an Antimalarial Drug
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Thomas Ruch, Elina Siirola, Radka Snajdrova
When designing the new route, aspects of how to increase yield, reduce cost, improve process safety and green metrics, had to be considered. It is clear that the low yield of a late stage Pictet-Spengler of amine 4 and 5-chloroisatine, had to be addressed. If starting from racemic tryptamine 4, all four diastereoisomers of the final product were formed, as the stereochemistry of the tryptamine set the stereochemistry of the spiroindolone system. In another words, if chiral amine S-4 could be used, only 2 out of 4 possible diastereoisomers would be formed—1R, 3S as the major diastereomer (KAE609) and the 1S, 3S as minor diastereomer (Scheme 15.5). This diastereoselectiviy can be rationalized by the avoidance of steric strain in the transition states leading to the diastereomers (Zhou, 2012). Stereochemistry of the Pictet-Spengler reaction.
Dihydroartemisinin–Piperaquine
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
PQP phosphate has also been combined with artemisinin (Artequick) (Krudsood et al., 2007), arterolane (Valecha et al., 2012), the ozonide OZ439 (Darpo et al., 2015) and the spiroindolone KAE609 (Cipargamin) (Stein et al., 2015), although clinical data are currently limited for these products that are either in the earlier stages of clinical development or have not received international regulatory approval.
Progress in Antimalarial Drug Discovery and Development
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Anna C.C. Aguiar, Wilian A. Cortopassi, Antoniana U. Krettli
MMV048 (18) is effective against resistant parasite strains across the entire parasite life cycle with the potential to cure and protect in a single dose. This medicine was the first new antimalarial to enter phase I studies in Africa (Paquet et al. 2017). The compound SJ733 (14) targets a Plasmodium cation-transporting ATPase, clearing parasites in vivo as quickly as ART (4) by specifically inducing eryptosis/senescence (Jiménez-Díaz et al. 2014a). The compound KAE609 (16) is a synthetic antimalarial drug belonging to the spiroindolone class that inhibits the P. falciparum Ca2+-ATPase (PfATP4). KAE609 (16) kills blood stages of P. falciparum in vitro at low nanomolar concentrations, including late-stage gametocytes, and thus possesses transmission-blocking activity potential (van Pelt-Koops et al. 2012). A phase I study has shown KAE609 (16) to be well tolerated in healthy volunteers at doses up to 150 mg daily and to have favorable pharmacokinetic properties (Leong et al. 2014). Furthermore, a phase II trial revealed the potent and fast activity of KAE609 (16) against both P. falciparum and P. vivax malaria, with a short mean parasite clearance time of 12 hr and a parasite half-life clearance of ~ 0.9 hr. Importantly, KAE609 (16) was highly effective for the treatment of patients infected with P. falciparum strains bearing mutations in the K13 gene (White et al. 2014). The DSM265(17) compound is an experimental antimalarial that selectively inhibits the parasite dihydroorotate dehydrogenase (DHODH). DSM265(17) shows in vitro activity against liver and blood stages of P. falciparum (Phillips et al. 2015).
Pharmacotherapy for artemisinin-resistant malaria
Published in Expert Opinion on Pharmacotherapy, 2021
Erik Koehne, Ayola Akim Adegnika, Jana Held, Andrea Kreidenweiss
Ganaplacide (KAF156), an imidazolpiperazine, and cipargamin (KAE609), a spiroindolone, are new antimalarial compounds currently in clinical development for the treatment of uncomplicated malaria and are currently in ongoing phase 2 trials. Ganaplacide and cipargamin were shown to be effective in vitro against P. falciparum with IC50s of 6–17.4 nM and 0.5 to 1.4 nM, respectively [119,120]. Currently, data from four published clinical trials exist for ganaplacide including a malaria challenge study [121–124]. Ganaplacide was well-tolerated when given at a daily dose of 400 mg for 3 days and a single dose of 800 mg, and had an overall 28-day cure rate of 67% in a small number of adults with uncomplicated P. vivax or P. falciparum malaria after single-dose administration [122]. Ganaplacide is currently developed in combination with lumefantrine [125] for a short treatment course. Data from seven clinical trials show cipargamin to be well-tolerated in healthy volunteers and in patients, however, there are some safety concerns in regard to liver function test abnormalities [126] A recently published malaria challenge trial reports antiplasmodial activity of a single dose, however liver safety signals appeared [127]. In a phase 2 trial done in Thailand, twenty-one patients with uncomplicated P. falciparum and P. vivax malaria were treated with a dose of 30 mg per day for three days and showed a parasite clearance half-life of less than 1 hour, that is even faster than artesunate [122,128]. Cipargamin is a promising candidate for a once-daily regimen.
A systems biology approach to antimalarial drug discovery
Published in Expert Opinion on Drug Discovery, 2018
Wilian Augusto Cortopassi, Tanos Celmar Costa Franca, Antoniana Ursine Krettli
Another promising antimalarial candidate with a known mechanism of action is the spiroindolone KAE609 [59]. This compound is an inhibitor of the PfATP4 enzyme and has advanced through initial clinical trial phases; it has also been shown to be cheaper and more potent than some currently used antimalarials such as artesunate and 4-aminoquinolines [60]. Interestingly, it is the first compound with a novel mechanism of action to achieve positive clinical proof-of-concept in over 20 years. Another inhibitor of the PfATP4 enzyme, (+)-SJ733, has also been identified and is currently being clinically investigated due to its potential of inducing rapid host-mediated Plasmodium clearance [61].