RESUMEN
Progress in the identification of suitable RORγ inverse agonists as clinical candidates has been hampered by the high lipophilicity that seems required for high potency on this nuclear receptor. In this context, we decided to focus on the replacement of the hydroxymethyl group found on known modulators to determine if more polarity could be tolerated in this position. SAR of the replacement of this moiety is presented in this article leading to the identification of sulfoximine derivatives as potent modulators with pharmacological activity in the in vivo mouse Imiquimod psoriasis model.
Asunto(s)
Iminas/farmacología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Sulfonamidas/farmacología , Sulfóxidos/farmacología , Animales , Agonismo Inverso de Drogas , Femenino , Humanos , Iminas/síntesis química , Iminas/química , Ligandos , Ratones Endogámicos BALB C , Estructura Molecular , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química , Sulfóxidos/síntesis química , Sulfóxidos/químicaRESUMEN
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.
Asunto(s)
Indazoles/química , Indazoles/farmacología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Agonismo Inverso de Drogas , Humanos , Simulación del Acoplamiento Molecular , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Relación Estructura-ActividadRESUMEN
With possible implications in multiple autoimmune diseases, the retinoic acid receptor-related orphan receptor RORγ has become a sought-after target in the pharmaceutical industry. Herein are described the efforts to identify a potent RORγ inverse agonist compatible with topical application for the treatment of skin diseases. These efforts culminated in the discovery of N-(2,4-dimethylphenyl)-N-isobutyl-2-oxo-1-[(tetrahydro-2H-pyran-4-yl)methyl]-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide (CD12681), a potent inverse agonist with inâ vivo activity in an IL-23-induced mouse skin inflammation model.