Open AccessConformational-Analysis-Guided Discovery of 2,3-Disubstituted Pyridine IDO1 Inhibitors
Author(s) -
Emily C. Cherney,
Liping Zhang,
Weiwei Guo,
Audris Huang,
David Williams,
Steven P. Seitz,
Weifang Shan,
Xiaohan Zhu,
Johnni Gullo-Brown,
Derrick Maley,
Tai-An Lin,
John T. Hunt,
Christine Huang,
Zheng Yang,
Celia D’Arienzo,
Lorell Discenza,
Asoka Ranasinghe,
Mary F. Grubb,
Sarah C. Traeger,
Xin Li,
Kathy Johnston,
Lisa M. Kopcho,
Mark Fereshteh,
Kimberly A. Foster,
Kevin Stefanski,
Diane Delpy,
Gopal Dhar,
Aravind Anandam,
Sandeep Mahankali,
Shweta Padmanabhan,
Prabhakar Rajanna,
Venkata Murali,
T. Thanga Mariappan,
Shabeerali Pattasseri,
Roshan Y. Nimje,
Zhenqiu Hong,
James Kempson,
Richard Rampulla,
Arvind Mathur,
Anuradha Gupta,
R. M. Borzilleri,
Gregory D. Vite,
Aaron Balog
Publication year - 2021
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.1c00236
Subject(s) - quinoline , chemistry , pharmacodynamics , pharmacology , small molecule , combinatorial chemistry , computational biology , drug discovery , pyridine , cancer research , pharmacokinetics , medicine , biochemistry , biology , medicinal chemistry , organic chemistry
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.