RESUMO
Optimization of our previously described pyrrolopiperidone series led to the identification of a new benzamide sub-series, which exhibits consistently high potency in biochemical and cell-based assays throughout the series. Strong inhibition of LPS-induced production of the cytokine TNFα is coupled to the regulation of HSP27 phosphorylation, indicating that the observed cellular effects result from the inhibition of MK2. X-ray crystallographic and computational analyses provide a rationale for the high potency of the series.
Assuntos
Benzamidas/farmacologia , Química Farmacêutica/métodos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/farmacologia , Piperidonas/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Simulação por Computador , Cristalografia por Raios X/métodos , Citocinas/metabolismo , Desenho de Fármacos , Proteínas de Choque Térmico HSP27/metabolismo , Proteínas de Choque Térmico , Humanos , Modelos Químicos , Chaperonas Moleculares , Fosforilação , Pirróis/químicaRESUMO
The identification of a potent, selective, and orally available MK2 inhibitor series is described. The initial absence of oral bioavailability was successfully tackled by moving the basic nitrogen of the spiro-4-piperidyl moiety towards the electron-deficient pyrrolepyridinedione core, thereby reducing the pK(a) and improving Caco-2 permeability. The resulting racemic spiro-3-piperidyl analogues were separated by chiral preparative HPLC, and the activity towards MK2 inhibition was shown to reside mostly in the first eluting stereoisomer. This led to the identification of new MK2 inhibitors, such as (S)-23, with low nanomolar biochemical inhibition (EC(50) 7.4 nM) and submicromolar cellular target engagement activity (EC(50) 0.5 µM).
Assuntos
Descoberta de Drogas , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Piperidinas/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Compostos de Espiro/síntese química , Administração Oral , Animais , Ligação Competitiva , Disponibilidade Biológica , Células CACO-2 , Cromatografia Líquida de Alta Pressão , Cristalografia por Raios X , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Peptídeos e Proteínas de Sinalização Intracelular/química , Estrutura Molecular , Piperidinas/química , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/química , Ratos , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
Here, we report the identification and optimization of 1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivatives as a novel chemotype with selective cannabinoid CB2 receptor agonist activity. 1 is a potent and selective cannabinoid CB2 receptor agonist (hCB2 pEC(50) = 8.6). The compound was found to be metabolically unstable, which resulted in low oral bioavailability in rat (F(po) = 4%) and possessed off-target activity at the hERG ion channel (pK(i) = 5.5). Systematic modification of physicochemical properties, such as lipophilicity and basicity, was used to optimize the pharmacokinetic profile and hERG affinity of this novel class of cannabinoid CB2 receptor agonists. This led to the identification of 44 as a potent, selective, and orally bioavailable cannabinoid CB2 receptor agonist (hCB2 pEC(50) = 8.0; hERG pK(i) < 4; F(po) = 100%), which was active in a rat spinal nerve ligation model of neuropathic pain.