Structure-activity relationship studies of orally active antimalarial 3,5-substituted 2-aminopyridines
In an effort to address potential cardiotoxicity liabilities identified with earlier frontrunner compounds, a number of new 3,5-diaryl-2-aminopyridine derivatives were synthesized. Several compounds exhibited potent antiplasmodial activity against both the multidrug resistant (K1) and sensitive (NF54) strains in the low nanomolar range. Some compounds displayed a significant reduction in potency in the hERG channel inhibition assay compared to previously reported frontrunner analogues. Several of these new analogues demonstrated promising in vivo efficacy in the Plasmodium berghei mouse model and will be further evaluated as potential clinical candidates. The SAR for in vitro antiplasmodial and hERG activity was delineated.
González Cabrera, Diego,Douelle, Frederic,Younis, Yassir,Feng, Tzu-Shean,Le Manach, Claire,Nchinda, Aloysius T.,Street, Leslie J.,Scheurer, Christian,Kamber, Jolanda,White, Karen L.,Montagnat, Oliver D.,Ryan, Eileen,Katneni, Kasiram,Zabiulla, K. Mohammed,Joseph, Jayan T.,Bashyam, Sridevi,Waterson, David,Witty, Michael J.,Charman, Susan A.,Wittlin, Sergio,Chibale, Kelly
p. 11022 - 11030
(2013/02/25)
NEW ANTI-MALARIAL AGENTS
The present invention is related to a use of aminopyridine derivatives in the manufacture of a medicament for preventing or treating malaria. Specifically, the present invention is related to aminopyridine derivatives useful for the preparation of a pharm
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Page/Page column 48
(2011/08/04)
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