786-27-6Relevant academic research and scientific papers
Structure-based Discovery of Phenyl (3-Phenylpyrrolidin-3-yl)sulfones as Selective, Orally Active RORγt Inverse Agonists
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
, p. 367 - 373 (2019)
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.
CARBOCYCLIC SULFONE RORγ MODULATORS
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Page/Page column 62, (2015/07/16)
Described are RORγ modulators of the formula (I), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein all substituents are defined herein. Also provided are pharmaceutical compositions comprising the same. Such compounds and compositions are useful in methods for modulating RORγ activity in a cell and methods for treating a subject suffering from a disease or disorder in which the subject would therapeutically benefit from modulation of RORγ activity, for example, autoimmune and/or inflammatory disorders.
PYRROLIDINYL SULFONE RORGAMMA MODULATORS
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Paragraph 0412-0413, (2015/07/15)
Described are RORγ modulators of the formula (I), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein all substituents are defined herein. Also provided are pharmaceutical compositions comprising the same. Such compounds and compositions are useful in methods for modulating RORγ activity in a cell and methods for treating a subject suffering from a disease or disorder in which the subject would therapeutically benefit from modulation of RORγ activity, for example, autoimmune and/or inflammatory disorders.
