학술논문
Oxetane Promise Delivered: Discovery of Long-Acting IDO1 Inhibitors Suitable for Q3W Oral or Parenteral Dosing
Document Type
Article
Author
Li, Derun; Sloman, David L.; Achab, Abdelghani; Zhou, Hua; McGowan, Meredeth A.; White, Catherine; Gibeau, Craig; Zhang, Hongjun; Pu, Qinglin; Bharathan, Indu; Hopkins, Brett; Liu, Kun; Ferguson, Heidi; Fradera, Xavier; Lesburg, Charles A.; Martinot, Theodore A.; Qi, Ji; Song, Zhiguo J.; Yin, Jingjun; Zhang, Huangguang; Song, Licheng; Wan, Baoqiang; DAddio, Suzanne; Solban, Nicolas; Miller, J. Richard; Zamlynny, Beata; Bass, Alan; Freeland, Elizabeth; Ykoruk, Bridget; Hilliard, Catherine; Ferraro, Jude; Zhai, Jin; Knemeyer, Ian; Otte, Karin M.; Vincent, Stella; Sciammetta, Nunzio; Pasternak, Alexander; Bennett, David Jonathan; Han, Yongxin
Source
Journal of Medicinal Chemistry; April 2022, Vol. 65 Issue: 8 p6001-6016, 16p
Subject
Language
ISSN
00222623; 15204804
Abstract
3,3-Disubstituted oxetanes have been utilized as bioisosteres for gem-dimethyl and cyclobutane functionalities. We report the discovery of a novel class of oxetane indole-amine 2,3-dioxygenase (IDO1) inhibitors suitable for Q3W (once every 3 weeks) oral and parenteral dosing. A diamide class of IDO inhibitors was discovered through an automated ligand identification system (ALIS). Installation of an oxetane and fluorophenyl dramatically improved the potency. Identification of a biaryl moiety as an unconventional amide isostere addressed the metabolic liability of amide hydrolysis. Metabolism identification (Met-ID)-guided target design and the introduction of polarity resulted in the discovery of potent IDO inhibitors with excellent pharmacokinetic (PK) profiles in multiple species. To enable rapid synthesis of the key oxetane intermediate, a novel oxetane ring cyclization was also developed, as well as optimization of a literature route on kg scale. These IDO inhibitors may enable unambiguous proof-of-concept testing for the IDO1 inhibition mechanism for oncology.