UCT943, a Next-Generation Plasmodium falciparum PI4K Inhibitor Preclinical Candidate for the Treatment of Malaria
Copyright © 2018 American Society for Microbiology..
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-2Rγ 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.
| Errataetall: |
ErratumIn: Antimicrob Agents Chemother. 2018 Oct 24;62(11):. - PMID 30355750 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2018 |
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| Erschienen: |
2018 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:62 |
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| Enthalten in: |
Antimicrobial agents and chemotherapy - 62(2018), 9 vom: 06. Sept. |
| Sprache: |
Englisch |
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| Links: |
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| Anmerkungen: |
Date Completed 26.09.2019 Date Revised 11.01.2023 published: Electronic-Print ErratumIn: Antimicrob Agents Chemother. 2018 Oct 24;62(11):. - PMID 30355750 Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1128/AAC.00012-18 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM285850423 |
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| 500 | |a Date Revised 11.01.2023 | ||
| 500 | |a published: Electronic-Print | ||
| 500 | |a ErratumIn: Antimicrob Agents Chemother. 2018 Oct 24;62(11):. - PMID 30355750 | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a Copyright © 2018 American Society for Microbiology. | ||
| 520 | |a 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-2Rγ 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a 1-phosphatidylinositol 4-kinase inhibitor | |
| 650 | 4 | |a Plasmodium spp. | |
| 650 | 4 | |a absorption | |
| 650 | 4 | |a distribution metabolism | |
| 650 | 4 | |a drug discovery | |
| 650 | 4 | |a excretion | |
| 650 | 4 | |a human dose prediction | |
| 650 | 4 | |a in vivo efficacy | |
| 650 | 4 | |a malaria | |
| 650 | 4 | |a pharmacokinetic/pharmacodynamic modeling | |
| 650 | 4 | |a pharmacokinetics | |
| 700 | 1 | |a Lawrence, Nina |e verfasserin |4 aut | |
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| 700 | 1 | |a Abay, Efrem |e verfasserin |4 aut | |
| 700 | 1 | |a Njoroge, Mathew |e verfasserin |4 aut | |
| 700 | 1 | |a Basarab, Gregory S |e verfasserin |4 aut | |
| 700 | 1 | |a Le Manach, Claire |e verfasserin |4 aut | |
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