1. Conformational-Analysis-Guided Discovery of 2,3-Disubstituted Pyridine IDO1 Inhibitors
- Author
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Lisa M. Kopcho, Johnni Gullo-Brown, Shweta Padmanabhan, Pattasseri Shabeerali, Arvind Mathur, Prabhakar Rajanna, Lorell Discenza, Liping Zhang, Zhenqiu Hong, Sarah C. Traeger, Zheng Yang, Cherney Emily Charlotte, Richard Rampulla, David K. Williams, Gopal Dhar, Kimberly A. Foster, James Kempson, Derrick Maley, Mary F. Grubb, Xiao Zhu, Xin Li, Weifang Shan, Robert M. Borzilleri, Diane Delpy, Kevin Stefanski, T. Thanga Mariappan, Gregory D. Vite, Kathy A. Johnston, Audris Huang, Asoka Ranasinghe, Mark Fereshteh, Aravind Anandam, Steven P. Seitz, John T. Hunt, Aaron Balog, Celia D’Arienzo, Anuradha Gupta, Tai-An Lin, Roshan Y. Nimje, Weiwei Guo, Christine Huang, Venkata Murali, and Sandeep Mahankali
- Subjects
chemistry.chemical_compound ,Oxidative metabolism ,chemistry ,Metastatic melanoma ,Mouse xenograft ,Organic Chemistry ,Drug Discovery ,Pyridine ,Quinoline ,Biochemistry ,Combinatorial chemistry - Abstract
[Image: see text] IDO1 inhibitors have shown promise as immunotherapies for the treatment of a variety of cancers, including metastatic melanoma and renal cell carcinoma. We recently reported the identification of several novel heme-displacing IDO1 inhibitors, including the clinical molecules linrodostat (BMS-986205) and BMS-986242. Both molecules contain quinolines that, while being present in successful medicines, are known to be potentially susceptible to oxidative metabolism. Efforts to swap this quinoline with an alternative aromatic system led to the discovery of 2,3-disubstituted pyridines as suitable replacements. Further optimization, which included lowering ClogP in combination with strategic fluorine incorporation, led to the discovery of compound 29, a potent, selective IDO1 inhibitor with robust pharmacodynamic activity in a mouse xenograft model.
- Published
- 2021