Discovery of phenoxyindazoles and phenylthioindazoles as RORγ inverse agonists

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• 作者：Gilles Ouvry^a ; ; Claire Bouix-Peter^a ; Fabrice Ciesielski^b ; Laurent Chantalat^a ; Olivier Christin^a ; Catherine Comino^a ; Denis Duvert^a ; Christophe Feret^a ; Craig S. Harris^a ; Laurent Lamy^a ; Anne-Pascale Luzy^a ; Branislav Musicki^a ; Danielle Orfila^a ; Jonathan Pascau^a ; Vé ; ronique Parnet^a ; Agn&egrave ; s Perrin^a ; Romain Pierre^a ; Gaë ; lle Polge^a ; Catherine Raffin^a ; Yves Rival^a ; Nathalie Taquet^a ; Etienne Thoreau^a ; Laurent F. Hennequin^a
• 关键词：PRFOAGMHUSKCKE-UHFFFAOYSA-N
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 December 2016
• 年：2016
• 卷：26
• 期：23
• 页码：5802-5808
• 全文大小：2646 K

文摘

Targeting the IL17 pathway and more specifically the nuclear receptor RORγ is thought to be beneficial in multiple skin disorders. The Letter describes the discovery of phenoxyindazoles and thiophenoxy indazoles as potent RORγ inverse agonists. Optimization of the potency and efforts to mitigate the phototoxic liability of the series are presented. Finally, crystallization of the lead compound revealed that the series bound to an allosteric site of the nuclear receptor. Such compounds could be useful as tool compounds for understanding the impact of topical treatment on skin disease models.