3,5-Diaryl-2-aminopyridines as a Novel Class of Orally Active Antimalarials Demonstrating Single Dose Cure in Mice and Clinical Candidate Potential

作者：Younis Yassir; Douelle Frederic; Feng Tzu Shean; Cabrera Diego Gonzalez; Le Manach Claire; Nchinda Aloysius T; Duffy Sandra; White Karen L; Shackleford David M; Morizzi Julia; Mannila Janne; Katneni Kasiram; Bhamidipati Ravi; Zabiulla K Mohammed; Joseph Jayan T; Bashyam Sridevi; Waterson David; Witty Michael J; Hardick David; Wittlin Sergio; Avery Vicky; Charman Susan A; Chibale Kelly^*

来源：Journal of Medicinal Chemistry, 2012, 55(7): 3479-3487.

DOI：10.1021/jm3001373

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 NFS4 (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 IS 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 (t(1/2) similar to 7-8 h).

• 出版日期2012-4-12