3,5-Diaryl-2-aminopyridines as a Novel Class of Orally Active Antimalarials Demonstrating Single Dose Cure in Mice and Clinical Candidate Potential
Abstract
A novel class of orally active antimalarial 3,5-diaryl-2-aminopyridines has been identified from phenotypic whole cell high-throughput screening of a commercially available SoftFocus kinase library. The compounds were evaluated in vitro for their antiplasmodial activity against K1 (chloroquine and drug-resistant strain) and NF54 (chloroquine-susceptible strain) as well as for their cytotoxicity. Synthesis and structure–activity studies identified a number of promising compounds with selective antiplasmodial activity. One of these frontrunner compounds, 15, was equipotent across the two strains (K1 = 25.0 nM, NF54 = 28.0 nM) and superior to chloroquine in the K1 strain (chloroquine IC50 K1 = 194.0 nM). Compound 15 completely cured Plasmodium berghei-infected mice with a single oral dose of 30 mg/kg. Dose–response studies generated ED50 and ED90 values of 0.83 and 1.74 mg/kg for 15 in the standard four-dose Peters test. Pharmacokinetic studies in the rat indicated that this compound has good oral bioavailability (51% at 20 mg/kg) and a reasonable half-life.
Citation
Younis, Y.; Douelle, F.; Feng TzuShean; González Cabrera, D.; Le Manach, C.; Nchinda, A.T.; Duffy, S.; White, K.L.; Shackleford, D.M.; Morizzi, J.; Mannila, J.; Katneni, K.; Bhamiddipati, R.; Zabiulla, M.; Joseph, J.T.; Bashyam, S.; Waterson, D.; Witty, M.J.; Hardick, D.; Wittlin, S.; Avery, V.; Charman, S.A.; Chibale, K. 3,5-Diaryl-2-aminopyridines as a Novel Class of Orally Active Antimalarials Demonstrating Single Dose Cure in Mice and Clinical Candidate Potential. Journal of Medicinal Chemistry (2012) 55 (7) 3479-3487. [DOI: 10.1021/jm3001373]