Identification of an aminothiazole series of RORβ modulators

[Display omitted] Crystallography has identified stearic acid, ALRT 1550 and ATRA as ligands that bind RORβ, however, none of these molecules represent good starting points to develop optimized small molecule modulators. Recently, Compound 1 was identified as a potent dual RORβ and RORγ inverse agon...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2018-04, Vol.28 (7), p.1178-1181
Main Authors: Patouret, Rémi, Doebelin, Christelle, Garcia-Ordonez, Ruben D., Chang, Mi Ra, Ruiz, Claudia, Cameron, Michael D., Griffin, Patrick R., Kamenecka, Theodore M.
Format: Article
Language:English
Subjects:
Aminothiazole
Dose-Response Relationship, Drug
Humans
Molecular Structure
Nuclear receptor
Nuclear Receptor Subfamily 1, Group F, Member 2 - agonists
RORβ
Selective ligand
Structure-Activity Relationship
Thiazoles - analysis
Thiazoles - chemistry
Thiazoles - pharmacology
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Summary:[Display omitted] Crystallography has identified stearic acid, ALRT 1550 and ATRA as ligands that bind RORβ, however, none of these molecules represent good starting points to develop optimized small molecule modulators. Recently, Compound 1 was identified as a potent dual RORβ and RORγ inverse agonist with no activity towards RORα (Fig. 1). To our knowledge, this is one of only two small molecule RORβ inverse agonists identified in the primary literature from a tractable chemical series and represents an ideal starting point from which to design RORβ-selective modulators. Herein we describe our SAR optimization efforts that led to a series of potent neutral antagonists of RORβ.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2018.03.001