870521-31-6Relevant articles and documents
3,5-Dialkoxypyridine analogues of bedaquiline are potent antituberculosis agents with minimal inhibition of the hERG channel
Sutherland, Hamish S.,Tong, Amy S.T.,Choi, Peter J.,Blaser, Adrian,Conole, Daniel,Franzblau, Scott G.,Lotlikar, Manisha U.,Cooper, Christopher B.,Upton, Anna M.,Denny, William A.,Palmer, Brian D.
supporting information, p. 1292 - 1307 (2019/02/25)
Bedaquiline is a new drug of the diarylquinoline class that has proven to be clinically effective against drug-resistant tuberculosis, but has a cardiac liability (prolongation of the QT interval) due to its potent inhibition of the cardiac potassium channel protein hERG. Bedaquiline is highly lipophilic and has an extremely long terminal half-life, so has the potential for more-than-desired accumulation in tissues during the relatively long treatment durations required to cure TB. The present work is part of a program that seeks to identify a diarylquinoline that is as potent as bedaquiline against Mycobacterium tuberculosis, with lower lipophilicity, higher clearance, and lower risk for QT prolongation. Previous work led to the identification of compounds with greatly-reduced lipophilicity compounds that retain good anti-tubercular activity in vitro and in mouse models of TB, but has not addressed the hERG blockade. We now present compounds where the C-unit naphthalene is replaced by a 3,5-dialkoxy-4-pyridyl, demonstrate more potent in vitro and in vivo anti-tubercular activity, with greatly attenuated hERG blockade. Two examples of this series are in preclinical development.
MK-8353: Discovery of an Orally Bioavailable Dual Mechanism ERK Inhibitor for Oncology
Boga, Sobhana Babu,Deng, Yongqi,Zhu, Liang,Nan, Yang,Cooper, Alan B.,Shipps, Gerald W.,Doll, Ronald,Shih, Neng-Yang,Zhu, Hugh,Sun, Robert,Wang, Tong,Paliwal, Sunil,Tsui, Hon-Chung,Gao, Xiaolei,Yao, Xin,Desai, Jagdish,Wang, James,Alhassan, Abdul Basit,Kelly, Joseph,Patel, Mehul,Muppalla, Kiran,Gudipati, Subrahmanyam,Zhang, Li-Kang,Buevich, Alexei,Hesk, David,Carr, Donna,Dayananth, Priya,Black, Stuart,Mei, Hong,Cox, Kathleen,Sherborne, Bradley,Hruza, Alan W.,Xiao, Li,Jin, Weihong,Long, Brian,Liu, Gongjie,Taylor, Stacey A.,Kirschmeier, Paul,Windsor, William T.,Bishop, Robert,Samatar, Ahmed A.
supporting information, p. 761 - 767 (2018/06/25)
The emergence and evolution of new immunological cancer therapies has sparked a rapidly growing interest in discovering novel pathways to treat cancer. Toward this aim, a novel series of pyrrolidine derivatives (compound 5) were identified as potent inhibitors of ERK1/2 with excellent kinase selectivity and dual mechanism of action but suffered from poor pharmacokinetics (PK). The challenge of PK was overcome by the discovery of a novel 3(S)-thiomethyl pyrrolidine analog 7. Lead optimization through focused structure-activity relationship led to the discovery of a clinical candidate MK-8353 suitable for twice daily oral dosing as a potential new cancer therapeutic.
SPIROCYCLIC COMPOUNDS
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Paragraph 0159, (2017/07/31)
Disclosed herein are spirocyclic compounds, together with pharmaceutical compositions and methods of ameliorating and/or treating a cancer described herein with one or more of the compounds described herein.
