Referenced in: none

Automatically associated channels: Kv11.1

Title: Structure-activity relationship studies of orally active antimalarial 3,5-substituted 2-aminopyridines.

Authors: Diego González Cabrera, Frederic Douelle, Yassir Younis, Tzu-Shean Feng, Claire Le Manach, Aloysius T Nchinda, Leslie J Street, Christian Scheurer, Jolanda Kamber, Karen L White, Oliver D Montagnat, Eileen Ryan, Kasiram Katneni, K Mohammed Zabiulla, Jayan T Joseph, Sridevi Bashyam, David Waterson, Michael J Witty, Susan A Charman, Sergio Wittlin, Kelly Chibale

Journal, date & volume: J. Med. Chem., 2012 Dec 27 , 55, 11022-30

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/23189922

Abstract
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.