1. Discovery of biaryls as RORγ inverse agonists by using structure-based design.
- Author
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Enyedy IJ, Powell NA, Caravella J, van Vloten K, Chao J, Banerjee D, Marcotte D, Silvian L, McKenzie A, Hong VS, and Fontenot JD
- Subjects
- Binding Sites, Crystallography, X-Ray, Drug Design, Hydrocarbons, Fluorinated pharmacology, Models, Molecular, Molecular Docking Simulation, Molecular Structure, Nuclear Receptor Subfamily 1, Group F, Member 3 chemistry, Nuclear Receptor Subfamily 1, Group F, Member 3 metabolism, Sulfonamides pharmacology, Hydrocarbons, Fluorinated chemistry, Nuclear Receptor Subfamily 1, Group F, Member 3 agonists, Structure-Activity Relationship, Sulfonamides chemistry
- Abstract
RORγ plays a critical role in controlling a pro-inflammatory gene expression program in several lymphocyte lineages including T cells, γδ T cells, and innate lymphoid cells. RORγ-mediated inflammation has been linked to susceptibility to Crohn's disease, arthritis, and psoriasis. Thus inverse agonists of RORγ have the potential of modulating inflammation. Our goal was to optimize two RORγ inverse agonists: T0901317 from literature and 1 that we obtained from internal screening. We used information from internal X-ray structures to design two libraries that led to a new biaryl series., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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