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UCT943, a next generation Plasmodium falciparum PI4K inhibitor preclinical candidate for the treatment of malaria

Brunschwig, Christel and Lawrence, Nina and Taylor, Dale and Abay, Efrem and Njoroge, Mathew and Basarab, Gregory S. and Le Manach, Claire and Paquet, Tanya and Cabrera, Diego Gonzàlez and Nchinda, Aloysius T. and de Kock, Carmen and Wiesner, Lubbe and Denti, Paolo and Waterson, David and Blasco, Benjamin and Leroy, Didier and Witty, Michael J. and Donini, Cristina and Duffy, James and Wittlin, Sergio and White, Karen L. and Charman, Susan A. and Jiménez-Díaz, Maria Belén and Angulo-Barturen, Iñigo and Herreros, Esperanza and Gamo, Francisco Javier and Rochford, Rosemary and Mancama, Dalu and Coetzer, Theresa L. and van der Watt, Mariëtte E. and Reader, Janette and Birkholtz, Lyn-Marie and Marsh, Kennan C. and Solapure, Suresh M. and Burke, John E. and McPhail, Jacob A. and Vanaerschot, Manu and Fidock, David A. and Fish, Paul V. and Siegl, Peter and Smith, Dennis A. and Wirjanata, Grennady and Noviyanti, Rintis and Price, Ric N. and Marfurt, Jutta and Silue, Kigbafori D. and Street, Leslie J. and Chibale, Kelly. (2018) UCT943, a next generation Plasmodium falciparum PI4K inhibitor preclinical candidate for the treatment of malaria. Antimicrobial agents and chemotherapy, 62 (9). e00012-e00018.

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Official URL: https://edoc.unibas.ch/65596/

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Abstract

The 2-aminopyridine MMV048 was the first drug candidate inhibiting; Plasmodium; phosphatidylinositol 4-kinase (PI4K), a novel drug target for malaria, to enter clinical development. In an effort to identify the next generation of PI4K inhibitors, the series was optimized to improve properties such as solubility and antiplasmodial potency across the parasite life cycle, leading to the 2-aminopyrazine UCT943. The compound displayed higher asexual blood stage, transmission-blocking, and liver stage activities than MMV048 and was more potent against resistant; Plasmodium falciparum; and; Plasmodium vivax; clinical isolates. Excellent; in vitro; antiplasmodial activity translated into high efficacy in; Plasmodium berghei; and humanized; P. falciparum; NOD-; scid IL-2R; γ; null; mouse models. The high passive permeability and high aqueous solubility of UCT943, combined with low to moderate; in vivo; intrinsic clearance, resulted in sustained exposure and high bioavailability in preclinical species. In addition, the predicted human dose for a curative single administration using monkey and dog pharmacokinetics was low, ranging from 50 to 80 mg. As a next-generation; Plasmodium; PI4K inhibitor, UCT943, based on the combined preclinical data, has the potential to form part of a single-exposure radical cure and prophylaxis (SERCaP) to treat, prevent, and block the transmission of malaria.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Wittlin, Sergio
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Society for Microbiology
ISSN:0066-4804
e-ISSN:1098-6596
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Identification Number:
Last Modified:12 Oct 2018 14:10
Deposited On:12 Oct 2018 14:10

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