| Autor: |
Mariana Lozano Gonzalez, Dennis J. Colussi, Tyler Eck, Samantha O. Aylor, Patty J. Lee, Shams Ul Mahmood, Tamara Kreiss, David P. Rotella, Brandon S. Pybus, Purnima Bhanot, Wayne E. Childers, John Gordon, Alison Roth, Rammohan R. Yadav Bheemanaboina, M. L. de Souza, John J. Siekierka |
| Rok vydání: |
2021 |
| Předmět: |
|
| DOI: |
10.1101/2021.08.24.457553 |
| Popis: |
The discovery of new targets for treatment of malaria 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, we recently reported the discovery and optimization of novel, potent isoxazole-based PfPKG inhibitors that lacked any obvious safety warnings. This manuscript presents representative in vitro ADME, hERG characterization and cell-based antiparasitic activity of these PfPKG inhibitors. We also report the discovery and structure-activity relationships of a new series with good potency, low hERG activity and cell-based anti-parasitic activity comparable to a literature standard. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
|
