Brunschwig, CLawrence, NTaylor, DAbay, ENjoroge, MBasarab, GSLe Manach, CPaquet, TCabrera, DGMancama, Dalubuhle T2018-12-112018-12-112018-09Brunschwig, C. et al. 2018. UCT943, a next-generation plasmodium falciparum PI4K inhibitor preclinical candidate for the treatment of malaria. Antimicrobial Agents and Chemotherapy: DOI: 10.1128/AAC.00012-180066-48041098-6596https://aac.asm.org/content/62/9/e00012-18doi: 10.1128/AAC.00012-18https://www.ncbi.nlm.nih.gov/pubmed/29941635http://hdl.handle.net/10204/10585The 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 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.en1-phosphatidylinositol 4-kinase inhibitorAbsorptionDistribution metabolismDrug discoveryExcretionHuman dose predictionIn vivo efficacyMalariaPharmacokinetic/pharmacodynamic modelingPharmacokineticsPlasmodium sppArticleBrunschwig, C., Lawrence, N., Taylor, D., Abay, E., Njoroge, M., Basarab, G., ... Mancama, D. T. (2018). UCT943, a next-generation plasmodium falciparum PI4K inhibitor preclinical candidate for the treatment of Malaria. http://hdl.handle.net/10204/10585Brunschwig, C, N Lawrence, D Taylor, E Abay, M Njoroge, GS Basarab, C Le Manach, T Paquet, DG Cabrera, and Dalubuhle T Mancama "UCT943, a next-generation plasmodium falciparum PI4K inhibitor preclinical candidate for the treatment of Malaria." (2018) http://hdl.handle.net/10204/10585Brunschwig C, Lawrence N, Taylor D, Abay E, Njoroge M, Basarab G, et al. UCT943, a next-generation plasmodium falciparum PI4K inhibitor preclinical candidate for the treatment of Malaria. 2018; http://hdl.handle.net/10204/10585.TY - Article AU - Brunschwig, C AU - Lawrence, N AU - Taylor, D AU - Abay, E AU - Njoroge, M AU - Basarab, GS AU - Le Manach, C AU - Paquet, T AU - Cabrera, DG AU - Mancama, Dalubuhle T AB - 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 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. DA - 2018-09 DB - ResearchSpace DP - CSIR KW - 1-phosphatidylinositol 4-kinase inhibitor KW - Absorption KW - Distribution metabolism KW - Drug discovery KW - Excretion KW - Human dose prediction KW - In vivo efficacy KW - Malaria KW - Pharmacokinetic/pharmacodynamic modeling KW - Pharmacokinetics KW - Plasmodium spp LK - https://researchspace.csir.co.za PY - 2018 SM - 0066-4804 SM - 1098-6596 T1 - UCT943, a next-generation plasmodium falciparum PI4K inhibitor preclinical candidate for the treatment of Malaria TI - UCT943, a next-generation plasmodium falciparum PI4K inhibitor preclinical candidate for the treatment of Malaria UR - http://hdl.handle.net/10204/10585 ER -