RESUMO
Mild reaction conditions for Petasis reactions of substituted salicylaldehydes with various amines and arylboronic acids in the presence of molecular sieves were developed. Molecular sieves (MS) significantly accelerated the reaction rates and drove the reactions to high conversions. The conditions were applied to the synthesis of the core structure of BIIB042, a γ-secretase modulator, without stereochemical erosion of a stereogenic center in the salicylaldehyde intermediate.
Assuntos
Aldeídos/química , Técnicas de Química Sintética , Aldeídos/síntese química , Aminas/química , Secretases da Proteína Precursora do Amiloide , Cromatografia Líquida de Alta Pressão , Espectroscopia de Ressonância Magnética , Estrutura Molecular , EstereoisomerismoRESUMO
Autoreactive B cell-derived antibodies form immune complexes that likely play a pathogenic role in autoimmune diseases. In systemic lupus erythematosus (SLE), these antibodies bind Fc receptors on myeloid cells and induce proinflammatory cytokine production by monocytes and NETosis by neutrophils. Bruton's tyrosine kinase (BTK) is a non-receptor tyrosine kinase that signals downstream of Fc receptors and plays a transduction role in antibody expression following B cell activation. Given the roles of BTK in both the production and sensing of autoreactive antibodies, inhibitors of BTK kinase activity may provide therapeutic value to patients suffering from autoantibody-driven immune disorders. Starting from an in-house proprietary screening hit followed by structure-based rational design, we have identified a potent, reversible BTK inhibitor, BIIB068 (1), which demonstrated good kinome selectivity with good overall drug-like properties for oral dosing, was well tolerated across preclinical species at pharmacologically relevant doses with good ADME properties, and achieved >90% inhibition of BTK phosphorylation (pBTK) in humans.
Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Pirimidinas/química , Administração Oral , Tirosina Quinase da Agamaglobulinemia/metabolismo , Animais , Antígenos T-Independentes/química , Antígenos T-Independentes/metabolismo , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Sítios de Ligação , Domínio Catalítico , Cães , Avaliação Pré-Clínica de Medicamentos , Feminino , Meia-Vida , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/metabolismo , Pirimidinas/uso terapêutico , Ratos , Relação Estrutura-AtividadeRESUMO
[reaction: see text] An efficient asymmetric synthesis of the vasopeptidase inhibitor BMS-189921 was accomplished. Two short enantioselective syntheses of the common key intermediate (S)-alpha-aminoazepinone 6b were developed. Olefin 3 was converted to 6b via asymmetric hydrogenation. Alternatively, enyne 12 was converted to racemic alpha-aminoazepinone 15b, which was transformed to 6b by a practical dynamic resolution.
Assuntos
Azepinas/química , Azepinas/síntese química , Endotélio Vascular/enzimologia , Inibidores Enzimáticos/síntese química , Neprilisina/antagonistas & inibidores , Azepinas/farmacologia , Inibidores Enzimáticos/farmacologia , Hidrogenação , EstereoisomerismoRESUMO
We have investigated a novel series of acid-derived γ-secretase modulators as a potential treatment of Alzheimer's disease. Optimization based on cellular potency and brain pharmacodynamics after oral dosing led to the discovery of 10a (BIIB042). Compound 10a is a potent γ-secretase modulator, which lowered Aß42, increased Aß38, but had little to no effect on Aß40 levels both in vitro and in vivo. In addition, compound 10a did not affect Notch signaling in our in vitro assessment. Compound 10a demonstrated excellent pharmacokinetic parameters in multiple species. Oral administration of 10a significantly reduced brain Aß42 levels in CF-1 mice and Fischer rats, as well as plasma Aß42 levels in cynomolgus monkeys. Compound 10a was selected as a candidate for preclinical safety evaluation.