3,5-Diaryl-2-aminopyridines as a Novel Class of Orally Active Antimalarials Demonstrating Single Dose Cure in Mice and Clinical Candidate Potential
Author(s)
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
Year published
2012
Metadata
Show full item recordAbstract
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 ...
View more >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 (t1/2 ~ 7-8 h).
View less >
View more >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 (t1/2 ~ 7-8 h).
View less >
Journal Title
Journal of Medicinal Chemistry
Volume
55
Issue
7
Copyright Statement
Self-archiving of the author-manuscript version is not yet supported by this journal. Please refer to the journal link for access to the definitive, published version or contact the authors for more information.
Subject
Medicinal and biomolecular chemistry
Organic chemistry
Biochemistry and cell biology not elsewhere classified
Pharmacology and pharmaceutical sciences