Structure鈥揂ctivity Relationship Studies of Orally Active Antimalarial 3,5-Substituted 2-Aminopyridines
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- 作者：Diego Gonz谩lez 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
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：December 27, 2012
- 年：2012
- 卷：55
- 期：24
- 页码：11022-11030
- 全文大小：385K
- 年卷期：v.55,no.24(December 27, 2012)
- ISSN：1520-4804
文摘
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.