RESUMO
A novel series of highly potent and selective p38 MAP kinase inhibitors was developed originating from a substituted N-aryl-6-pyrimidinone scaffold. SAR studies coupled with in vivo evaluations in rat arthritis model culminated in the identification of 10 with excellent oral efficacy. Compound 10 exhibited a significantly enhanced dissolution rate compared to 1, translating to a high oral bioavailability (>90%) in rat. In animal studies 10 inhibited LPS-stimulated production of tumor necrosis factor-α in a dose-dependent manner and demonstrated robust efficacy comparable to dexamethasone in a rat streptococcal cell wall-induced arthritis model.
Assuntos
Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinonas/uso terapêutico , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Administração Oral , Animais , Artrite/tratamento farmacológico , Artrite Experimental , Células CACO-2 , Cristalografia por Raios X , Humanos , Concentração Inibidora 50 , Masculino , Modelos Moleculares , Inibidores de Proteínas Quinases/química , Pirimidinonas/química , Ratos , Ratos Endogâmicos Lew , Relação Estrutura-AtividadeRESUMO
Herein we report the identification of two new fatty acid amide hydrolase (FAAH) inhibitor lead series with FAAH k(inact)/K(i) potency values greater than 1500M(-1)s(-1). The two novel spirocyclic cores, 7-azaspiro[3.5]nonane and 1-oxa-8-azaspiro[4.5]decane, clearly distinguished themselves from the other spirocyclic cores on the basis of their superior potency for FAAH. Lead compounds from these two series have suitable FAAH potency and selectivity for additional medicinal chemistry optimization.
Assuntos
Amidoidrolases/antagonistas & inibidores , Compostos Aza/farmacologia , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Compostos de Espiro/farmacologia , Compostos Aza/química , Inibidores Enzimáticos/química , Modelos Moleculares , Compostos de Espiro/química , Relação Estrutura-AtividadeRESUMO
The synthesis and SAR studies of a novel N-aryl pyridinone class of p38 kinase inhibitors are described. Systematic structural modifications to the HTS lead, 5, led to the identification of (-)-4a as a clinical candidate for the treatment of inflammatory diseases. Additionally, the chiral synthesis and properties of (-)-4a are described.
Assuntos
Benzamidas/síntese química , Benzamidas/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Pironas/síntese química , Pironas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Benzamidas/química , Modelos Animais de Doenças , Cães , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Macaca fascicularis , Masculino , Estrutura Molecular , Piridonas , Pironas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Proteínas Quinases p38 Ativadas por Mitógeno/química , Proteínas Quinases p38 Ativadas por Mitógeno/farmacologiaRESUMO
A series of N-aryl pyridinone inhibitors of p38 mitogen activated protein (MAP) kinase were designed and prepared based on the screening hit SC-25028 (1) and structural comparisons to VX-745 (5). The focus of the investigation targeted the dependence of potency and metabolic stability on the benzyloxy connectivity, the role of the C-6 position and the substitution pattern on the N-phenyl ring. Further optimization produced the highly selective and potent pyridinones 2 and 3. These inhibitors exhibited activity in both acute and chronic models of inflammation.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Piridonas/síntese química , Piridonas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Masculino , Microssomos Hepáticos/enzimologia , Estrutura Molecular , Piridazinas/química , Piridazinas/farmacologia , Piridonas/química , Pirimidinas/química , Pirimidinas/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
Fatty acid amide hydrolase (FAAH) has attracted significant attention due to its promise as an analgesic target. This has resulted in the discovery of numerous chemical classes as inhibitors of this potential therapeutic target. In this paper we disclose a new series of novel FAAH irreversible azetidine urea inhibitors. In general these compounds illustrate potent activity against the rat FAAH enzyme. Our SAR studies allowed us to optimize this series resulting in the identification of compounds 13 which were potent inhibitors of both human and rat enzyme. This series of compounds illustrated good hydrolase selectivity along with good PK properties.
Assuntos
Amidoidrolases/antagonistas & inibidores , Analgésicos/química , Azetidinas/química , Inibidores Enzimáticos/química , Piridazinas/química , Ureia/química , Amidoidrolases/metabolismo , Analgésicos/síntese química , Analgésicos/farmacocinética , Animais , Azetidinas/síntese química , Azetidinas/farmacocinética , Sítios de Ligação , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Humanos , Piridazinas/síntese química , Piridazinas/farmacocinética , Ratos , Relação Estrutura-Atividade , Ureia/síntese química , Ureia/farmacocinéticaRESUMO
The identification and evolution of a series of potent and selective p38 inhibitors is described. p38 inhibitors based on a N-benzyl pyridinone high-throughput screening hit were prepared and their SAR explored. Their design was guided by ligand bound co-crystals of p38alpha. These efforts resulted in the identification of 12r and 19 as orally active inhibitors of p38 with significant efficacy in both acute and chronic models of inflammation.