Conformational-Analysis-Guided Discovery of 2,3-Disubstituted Pyridine IDO1 Inhibitors.

Autor:	Cherney EC; Bristol Myers Squibb Research and Development, 3551 Lawrenceville, Princeton Road, Lawrence Township, New Jersey 08648, United States., Zhang L; Bristol Myers Squibb Research and Development, 3551 Lawrenceville, Princeton Road, Lawrence Township, New Jersey 08648, United States., Guo W; Bristol Myers Squibb Research and Development, 3551 Lawrenceville, Princeton Road, Lawrence Township, New Jersey 08648, United States., Huang A; Bristol Myers Squibb Research and Development, 3551 Lawrenceville, Princeton Road, Lawrence Township, New Jersey 08648, United States., Williams D; Bristol Myers Squibb Research and Development, 3551 Lawrenceville, Princeton Road, Lawrence Township, New Jersey 08648, United States., Seitz S; Bristol Myers Squibb Research and Development, 3551 Lawrenceville, Princeton Road, Lawrence Township, New Jersey 08648, United States., Shan W; Bristol Myers Squibb Research and Development, 3551 Lawrenceville, Princeton Road, Lawrence Township, New Jersey 08648, United States., Zhu X; Bristol Myers Squibb Research and Development, 3551 Lawrenceville, Princeton Road, Lawrence Township, New Jersey 08648, United States., Gullo-Brown J; Bristol Myers Squibb Research and Development, 3551 Lawrenceville, Princeton Road, Lawrence Township, New Jersey 08648, United States., Maley D; Bristol Myers Squibb Research and Development, 3551 Lawrenceville, Princeton Road, Lawrence Township, New Jersey 08648, United States., Lin TA; Bristol Myers Squibb Research and Development, 3551 Lawrenceville, Princeton Road, Lawrence Township, New Jersey 08648, United States., Hunt JT; Bristol Myers Squibb Research and Development, 3551 Lawrenceville, Princeton Road, Lawrence Township, New Jersey 08648, United States., Huang C; Bristol Myers Squibb Research and Development, 3551 Lawrenceville, Princeton Road, Lawrence Township, New Jersey 08648, United States., Yang Z; Bristol Myers Squibb Research and Development, 3551 Lawrenceville, Princeton Road, Lawrence Township, New Jersey 08648, United States., D'Arienzo CJ; Bristol Myers Squibb Research and Development, 3551 Lawrenceville, Princeton Road, Lawrence Township, New Jersey 08648, United States., Discenza LN; Bristol Myers Squibb Research and Development, 3551 Lawrenceville, Princeton Road, Lawrence Township, New Jersey 08648, United States., Ranasinghe A; Bristol Myers Squibb Research and Development, 3551 Lawrenceville, Princeton Road, Lawrence Township, New Jersey 08648, United States., Grubb MF; Bristol Myers Squibb Research and Development, 3551 Lawrenceville, Princeton Road, Lawrence Township, New Jersey 08648, United States., Traeger SC; Bristol Myers Squibb Research and Development, 3551 Lawrenceville, Princeton Road, Lawrence Township, New Jersey 08648, United States., Li X; Bristol Myers Squibb Research and Development, 3551 Lawrenceville, Princeton Road, Lawrence Township, New Jersey 08648, United States., Johnston KA; Bristol Myers Squibb Research and Development, 3551 Lawrenceville, Princeton Road, Lawrence Township, New Jersey 08648, United States., Kopcho L; Bristol Myers Squibb Research and Development, 3551 Lawrenceville, Princeton Road, Lawrence Township, New Jersey 08648, United States., Fereshteh M; Bristol Myers Squibb Research and Development, 3551 Lawrenceville, Princeton Road, Lawrence Township, New Jersey 08648, United States., Foster KA; Bristol Myers Squibb Research and Development, 3551 Lawrenceville, Princeton Road, Lawrence Township, New Jersey 08648, United States., Stefanski K; Bristol Myers Squibb Research and Development, 3551 Lawrenceville, Princeton Road, Lawrence Township, New Jersey 08648, United States., Delpy D; Bristol Myers Squibb Research and Development, 3551 Lawrenceville, Princeton Road, Lawrence Township, New Jersey 08648, United States., Dhar G; Department of Discovery Synthesis, Biocon Bristol Myers Squibb R&D Centre, Syngene International Ltd., Biocon Park, Plot No. 2 & 3, Bommasandra-Jigani Road, Bangalore 560099, India., Anandam A; Department of Discovery Synthesis, Biocon Bristol Myers Squibb R&D Centre, Syngene International Ltd., Biocon Park, Plot No. 2 & 3, Bommasandra-Jigani Road, Bangalore 560099, India., Mahankali S; Department of Discovery Synthesis, Biocon Bristol Myers Squibb R&D Centre, Syngene International Ltd., Biocon Park, Plot No. 2 & 3, Bommasandra-Jigani Road, Bangalore 560099, India., Padmanabhan S; Department of Discovery Synthesis, Biocon Bristol Myers Squibb R&D Centre, Syngene International Ltd., Biocon Park, Plot No. 2 & 3, Bommasandra-Jigani Road, Bangalore 560099, India., Rajanna P; Department of Discovery Synthesis, Biocon Bristol Myers Squibb R&D Centre, Syngene International Ltd., Biocon Park, Plot No. 2 & 3, Bommasandra-Jigani Road, Bangalore 560099, India., Murali V; Department of Discovery Synthesis, Biocon Bristol Myers Squibb R&D Centre, Syngene International Ltd., Biocon Park, Plot No. 2 & 3, Bommasandra-Jigani Road, Bangalore 560099, India., Mariappan TT; Department of Discovery Synthesis, Biocon Bristol Myers Squibb R&D Centre, Syngene International Ltd., Biocon Park, Plot No. 2 & 3, Bommasandra-Jigani Road, Bangalore 560099, India., Pattasseri S; Department of Discovery Synthesis, Biocon Bristol Myers Squibb R&D Centre, Syngene International Ltd., Biocon Park, Plot No. 2 & 3, Bommasandra-Jigani Road, Bangalore 560099, India., Nimje RY; Department of Discovery Synthesis, Biocon Bristol Myers Squibb R&D Centre, Syngene International Ltd., Biocon Park, Plot No. 2 & 3, Bommasandra-Jigani Road, Bangalore 560099, India., Hong Z; Bristol Myers Squibb Research and Development, 3551 Lawrenceville, Princeton Road, Lawrence Township, New Jersey 08648, United States., Kempson J; Bristol Myers Squibb Research and Development, 3551 Lawrenceville, Princeton Road, Lawrence Township, New Jersey 08648, United States., Rampulla R; Bristol Myers Squibb Research and Development, 3551 Lawrenceville, Princeton Road, Lawrence Township, New Jersey 08648, United States., Mathur A; Bristol Myers Squibb Research and Development, 3551 Lawrenceville, Princeton Road, Lawrence Township, New Jersey 08648, United States., Gupta A; Department of Discovery Synthesis, Biocon Bristol Myers Squibb R&D Centre, Syngene International Ltd., Biocon Park, Plot No. 2 & 3, Bommasandra-Jigani Road, Bangalore 560099, India., Borzilleri R; Bristol Myers Squibb Research and Development, 3551 Lawrenceville, Princeton Road, Lawrence Township, New Jersey 08648, United States., Vite G; Bristol Myers Squibb Research and Development, 3551 Lawrenceville, Princeton Road, Lawrence Township, New Jersey 08648, United States., Balog A; Bristol Myers Squibb Research and Development, 3551 Lawrenceville, Princeton Road, Lawrence Township, New Jersey 08648, United States.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2021 Jun 16; Vol. 12 (7), pp. 1143-1150. Date of Electronic Publication: 2021 Jun 16 (Print Publication: 2021).
DOI:	10.1021/acsmedchemlett.1c00236
Abstrakt:	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.)
Databáze:	MEDLINE
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