Pharmacokinetics and In Vivo Efficacy of Pyrazolopyrimidine, Pyrrolopyrimidine, and 5-Aminopyrazole-4-Carboxamide Bumped Kinase Inhibitors against Toxoplasmosis
2019
Hulverson, Matthew A | Bruzual, Igor | McConnell, Erin V | Huang, Wenlin | Vidadala, Rama S R | Choi, Ryan | Arnold, Samuel L M | Whitman, Grant R | McCloskey, Molly C | Barrett, Lynn K | Rivas, Kasey L | Scheele, Suzanne | DeRocher, Amy E | Parsons, Marilyn | Ojo, Kayode K | Maly, Dustin J. | Fan, Erkang | Van Voorhis, Wesley C. | Doggett, J Stone
Bumped kinase inhibitors (BKIs) have been shown to be potent inhibitors of Toxoplasma gondii calcium-dependent protein kinase 1. Pyrazolopyrimidine and 5-aminopyrazole-4-carboxamide scaffold-based BKIs are effective in acute and chronic experimental models of toxoplasmosis. Through further exploration of these 2 scaffolds and a new pyrrolopyrimidine scaffold, additional compounds have been identified that are extremely effective against acute experimental toxoplasmosis. The in vivo efficacy of these BKIs demonstrates that the cyclopropyloxynaphthyl, cyclopropyloxyquinoline, and 2-ethoxyquinolin-6-yl substituents are associated with efficacy across scaffolds. In addition, a broad range of plasma concentrations after oral dosing resulted from small structural changes to the BKIs. These select BKIs include anti-Toxoplasma compounds that are effective against acute experimental toxoplasmosis and are not toxic in human cell assays, nor to mice when administered for therapy. The BKIs described here are promising late leads for improving anti-Toxoplasma therapy.
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