1. Conformational-Analysis-Guided Discovery of 2,3-Disubstituted Pyridine IDO1 Inhibitors.
- Author
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Cherney EC, Zhang L, Guo W, Huang A, Williams D, Seitz S, Shan W, Zhu X, Gullo-Brown J, Maley D, Lin TA, Hunt JT, Huang C, Yang Z, D'Arienzo CJ, Discenza LN, Ranasinghe A, Grubb MF, Traeger SC, Li X, Johnston KA, Kopcho L, Fereshteh M, Foster KA, Stefanski K, Delpy D, Dhar G, Anandam A, Mahankali S, Padmanabhan S, Rajanna P, Murali V, Mariappan TT, Pattasseri S, Nimje RY, Hong Z, Kempson J, Rampulla R, Mathur A, Gupta A, Borzilleri R, Vite G, and Balog A
- 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., Competing Interests: The authors declare no competing financial interest., (© 2021 American Chemical Society.)
- Published
- 2021
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