| Literature DB >> 34267885 |
Emily C Cherney1, Liping Zhang1, Weiwei Guo1, Audris Huang1, David Williams1, Steven Seitz1, Weifang Shan1, Xiao Zhu1, Johnni Gullo-Brown1, Derrick Maley1, Tai-An Lin1, John T Hunt1, Christine Huang1, Zheng Yang1, Celia J D'Arienzo1, Lorell N Discenza1, Asoka Ranasinghe1, Mary F Grubb1, Sarah C Traeger1, Xin Li1, Kathy A Johnston1, Lisa Kopcho1, Mark Fereshteh1, Kimberly A Foster1, Kevin Stefanski1, Diane Delpy1, Gopal Dhar2, Aravind Anandam2, Sandeep Mahankali2, Shweta Padmanabhan2, Prabhakar Rajanna2, Venkata Murali2, T Thanga Mariappan2, Shabeerali Pattasseri2, Roshan Y Nimje2, Zhenqiu Hong1, James Kempson1, Richard Rampulla1, Arvind Mathur1, Anuradha Gupta2, Robert Borzilleri1, Gregory Vite1, Aaron Balog1.
Abstract
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.Entities:
Year: 2021 PMID： 34267885 PMCID： PMC8274105 DOI： 10.1021/acsmedchemlett.1c00236
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.632