期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 12, 期 12, 页码 1962-1967出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.1c00540
关键词
Malaria; protein kinase inhibitor; PfPKG inhibitor; cellular activity; P. falciparum drug target
资金
- Sokol Institute for Pharmaceutical Life Sciences
- National Institutes of Health [RO1-AI-133633-01]
- Military Infectious Disease Research Program [Q0480_19_WR_CS_OC]
This paper presents initial structure-activity relationships in an imidazole scaffold at four positions, representative in vitro ADME, hERG characterization, and cell-based antiparasitic activity.
The discovery of new targets for the treatment of malaria, in particular those aimed at the pre-erythrocytic stage in the life cycle, advanced with the demonstration that orally administered inhibitors of Plasmodium falciparum cGMP-dependent protein kinase (PfPKG) could clear infection in a murine model. This enthusiasm was tempered by unsatisfactory safety and/or pharmacokinetic issues found with these chemotypes. To address the urgent need for new scaffolds, this paper presents initial structure-activity relationships in an imidazole scaffold at four positions, representative in vitro ADME, hERG characterization, and cell-based antiparasitic activity. This series of PfPKG inhibitors has good in vitro PfPKG potency, low hERG activity, and cell-based antiparasitic activity against multiple Plasmodium species that appears to be correlated with the in vitro potency.
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