RESUMO
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.
Assuntos
Iminas/farmacologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Sulfonamidas/farmacologia , Sulfóxidos/farmacologia , Animais , Agonismo Inverso de Drogas , Feminino , Humanos , Iminas/síntese química , Iminas/química , Ligantes , Camundongos Endogâmicos BALB C , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfóxidos/síntese química , Sulfóxidos/químicaRESUMO
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.
Assuntos
Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Psoríase/tratamento farmacológico , Sulfonamidas/química , Administração Tópica , Animais , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Agonismo Inverso de Drogas , Humanos , Concentração Inibidora 50 , Interleucina-17/metabolismo , Interleucina-23/farmacologia , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Psoríase/patologia , Dermatopatias/induzido quimicamente , Dermatopatias/tratamento farmacológico , Dermatopatias/patologia , Relação Estrutura-Atividade , Sulfonamidas/metabolismo , Sulfonamidas/uso terapêutico , Células Th17/citologia , Células Th17/efeitos dos fármacos , Células Th17/metabolismoRESUMO
Targeting the TNFα pathway is a validated approach to the treatment of psoriasis. In this pathway, TACE stands out as a druggable target and has been the focus of in-house research programs. In this article, we present the discovery of clinical candidate 26a. Starting from hits plagued with poor solubility or genotoxicity, 26a was identified through thorough multiparameter optimisation. Showing robust in vivo activity in an oxazolone-mediated inflammation model, the compound was selected for development. Following a polymorph screen, the hydrochloride salt was selected and the synthesis was efficiently developed to yield the API in 47% overall yield.