RESUMO
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.
Assuntos
Proteína ADAM17/antagonistas & inibidores , Inibidores Enzimáticos/química , Proteína ADAM17/metabolismo , Administração Tópica , Animais , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Ácidos Hidroxâmicos/química , Camundongos , Camundongos Pelados , Microssomos Hepáticos/metabolismo , Oxazolona/toxicidade , Psoríase/tratamento farmacológico , Psoríase/patologia , Dermatopatias/induzido quimicamente , Dermatopatias/prevenção & controle , Dermatopatias/veterinária , Solubilidade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Targeting the Tumor Necrosis Factor α signalling with antibodies has led to a revolution in the treatment of psoriasis. Locally inhibiting Tumor Necrosis Factor α Converting Enzyme (TACE or ADAM17) could potentially mimic those effects and help treat mild to moderate psoriasis, without the reported side effect of systemic TACE inhibitors. Efforts to identify new TACE inhibitors are presented here. Enzymatic SAR as well as ADME and physico-chemistry data are presented. This study culminated in the identification of potent enzymatic inhibitors. Suboptimal cellular activity of this series is discussed in the context of previously published results.
Assuntos
Proteína ADAM17/antagonistas & inibidores , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Ácidos Hidroxâmicos/administração & dosagem , Ácidos Hidroxâmicos/química , Proteína ADAM17/metabolismo , Administração Tópica , Humanos , Psoríase/tratamento farmacológico , Psoríase/enzimologiaRESUMO
Minor structural modifications-sometimes single atom changes-can have a dramatic impact on the properties of compounds. This is illustrated here on structures related to known mTOR inhibitor Sapanisertib. Subtle changes in the hinge binder lead to strikingly different overall profiles with changes in physical properties, metabolism, and kinase selectivity.