RESUMO
Amyotrophic lateral sclerosis (ALS) is a poorly treated multifactorial neurodegenerative disease associated with multiple cell types and subcellular organelles. As with other multifactorial diseases, it is likely that drugs will need to target multiple disease processes and cell types to be effective. We review here the role of Janus kinase (JAK)/Signal transducer and activator of transcription (STAT) signalling in ALS, confirm the association of this signalling with fundamental ALS disease processes using the BenevolentAI Knowledge Graph, and demonstrate that inhibitors of this pathway could reduce the ALS pathophysiology in neurons, glia, muscle fibres, and blood cells. Specifically, we suggest that inhibition of the JAK enzymes by approved inhibitors known as Jakinibs could reduce STAT3 activation and modify the progress of this disease. Analysis of the Jakinibs highlights baricitinib as a suitable candidate due to its ability to penetrate the central nervous system and exert beneficial effects on the immune system. Therefore, we recommend that this drug be tested in appropriately designed clinical trials for ALS.
Assuntos
Esclerose Lateral Amiotrófica , Inibidores de Janus Quinases , Doenças Neurodegenerativas , Humanos , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Inibidores de Janus Quinases/uso terapêutico , Sistema Nervoso Central/metabolismo , Janus Quinases/metabolismo , Janus Quinases/uso terapêuticoRESUMO
Efficient syntheses of both enantiomers of a spirodiamine diester from (l)- and (d)-aspartic acid are described. The key transformation was the conversion of Boc-protected tert-butyl aspartate into the derived aldehyde, two-directional Horner-Wadsworth-Emmons olefination, hydrogenation, and selective acid-catalyzed Boc-deprotection and spirocyclization. An alternative, two-directional approach to derivatives of 1,7-diazaspiro[5.5]undecane is described.
RESUMO
Suzuki-Miyaura cross-coupling reactions of heteroaryl polyhalides with aryl boronates are surveyed. Drawing on data from literature sources as well as bespoke searches of Pfizer's global chemistry RKB and CAS Scifinder® databases, the factors that determine the site-selectivity of these reactions are discussed with a view to rationalising the trends found.
RESUMO
An efficient two-step synthesis of symmetrical and unsymmetrical tetrahydrospirobiquinolines from o-azidobenzaldehydes is reported. A novel series of tetrahydrospirobiquinolines was prepared by sequential double-aldol condensation with acetone, cyclopentanone, and cyclohexanone to form the corresponding o,o'-diazido-dibenzylidene-acetone, -cyclopentanone, and -cyclohexanone derivatives, respectively, and hydrogenation-spirocyclization. The spirodiamines were further derivatized by electrophilic aromatic bromination, Suzuki coupling, and N-alkylation, all of which proceeded with preservation of the spirocyclic core.