ACS Medicinal Chemistry Letters p. 367 - 373 (2019)
Update date:2022-08-05
Topics:
Duan, James J.-W.
Lu, Zhonghui
Jiang, Bin
Stachura, Sylwia
Weigelt, Carolyn A.
Sack, John S.
Khan, Javed
Ruzanov, Max
Galella, Michael A.
Wu, Dauh-Rurng
Yarde, Melissa
Shen, Ding-Ren
Shuster, David J.
Borowski, Virna
Xie, Jenny H.
Zhang, Lisa
Vanteru, Sridhar
Gupta, Arun Kumar
Mathur, Arvind
Zhao, Qihong
Foster, William
Salter-Cid, Luisa M.
Carter, Percy H.
Dhar, T. G. Murali
A new phenyl (3-phenylpyrrolidin-3-yl)sulfone series of RORγt inverse agonists was discovered utilizing the binding conformation of previously reported bicyclic sulfonamide 1. Through a combination of structure-based design and structure-activity relationship studies, a polar set of amides at N1-position of the pyrrolidine ring and perfluoroisopropyl group at para-position of the 3-phenyl group were identified as critical structural elements to achieve high selectivity against PXR, LXRα, and LXRβ. Further optimization led to the discovery of (1R,4r)-4-((R)-3-((4-fluorophenyl)sulfonyl)-3-(4-(perfluoropropan-2-yl)phenyl)pyrrolidine-1-carbonyl)cyclohexane-1-carboxylic acid (26), which displayed excellent selectivity, desirable liability and pharmacokinetic properties in vitro, and a good pharmacokinetic profile in mouse. Oral administration of 26 demonstrated dose-dependent inhibition of IL-17 production in a mouse IL-2/IL-23-induced pharmacodynamic model and biologic-like efficacy in an IL-23-induced mouse acanthosis model.
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