Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 3 de 3
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Nat Chem ; 16(2): 239-248, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37996732

RESUMO

Late-stage functionalization is an economical approach to optimize the properties of drug candidates. However, the chemical complexity of drug molecules often makes late-stage diversification challenging. To address this problem, a late-stage functionalization platform based on geometric deep learning and high-throughput reaction screening was developed. Considering borylation as a critical step in late-stage functionalization, the computational model predicted reaction yields for diverse reaction conditions with a mean absolute error margin of 4-5%, while the reactivity of novel reactions with known and unknown substrates was classified with a balanced accuracy of 92% and 67%, respectively. The regioselectivity of the major products was accurately captured with a classifier F-score of 67%. When applied to 23 diverse commercial drug molecules, the platform successfully identified numerous opportunities for structural diversification. The influence of steric and electronic information on model performance was quantified, and a comprehensive simple user-friendly reaction format was introduced that proved to be a key enabler for seamlessly integrating deep learning and high-throughput experimentation for late-stage functionalization.


Assuntos
Aprendizado Profundo , Ensaios de Triagem em Larga Escala
2.
J Med Chem ; 63(18): 10287-10306, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32787079

RESUMO

Despite the broad implications of the cannabinoid type 2 receptor (CB2) in neuroinflammatory processes, a suitable CB2-targeted probe is currently lacking in clinical routine. In this work, we synthesized 15 fluorinated pyridine derivatives and tested their binding affinities toward CB2 and CB1. With a sub-nanomolar affinity (Ki for CB2) of 0.8 nM and a remarkable selectivity factor of >12,000 over CB1, RoSMA-18-d6 exhibited outstanding in vitro performance characteristics and was radiofluorinated with an average radiochemical yield of 10.6 ± 3.8% (n = 16) and molar activities ranging from 52 to 65 GBq/µmol (radiochemical purity > 99%). [18F]RoSMA-18-d6 showed exceptional CB2 attributes as demonstrated by in vitro autoradiography, ex vivo biodistribution, and positron emission tomography (PET). Further, [18F]RoSMA-18-d6 was used to detect CB2 upregulation on postmortem human ALS spinal cord tissues. Overall, these results suggest that [18F]RoSMA-18-d6 is a promising CB2 PET radioligand for clinical translation.


Assuntos
Piridinas/farmacologia , Compostos Radiofarmacêuticos/farmacologia , Receptor CB2 de Canabinoide/metabolismo , Animais , Encéfalo/diagnóstico por imagem , Radioisótopos de Flúor/química , Humanos , Ligantes , Masculino , Simulação de Acoplamento Molecular , Estrutura Molecular , Tomografia por Emissão de Pósitrons , Piridinas/síntese química , Piridinas/farmacocinética , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Ratos Wistar , Medula Espinal/diagnóstico por imagem , Baço/diagnóstico por imagem , Relação Estrutura-Atividade , Trítio/química
3.
J Med Chem ; 62(24): 11165-11181, 2019 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-31751140

RESUMO

The cannabinoid type 2 (CB2) receptor has emerged as a valuable target for therapy and imaging of immune-mediated pathologies. With the aim to find a suitable radiofluorinated analogue of the previously reported CB2 positron emission tomography (PET) radioligand [11C]RSR-056, 38 fluorinated derivatives were synthesized and tested by in vitro binding assays. With a Ki (hCB2) of 6 nM and a selectivity factor of nearly 700 over cannabinoid type 1 receptors, target compound 3 exhibited optimal in vitro properties and was selected for evaluation as a PET radioligand. [18F]3 was obtained in an average radiochemical yield of 11 ± 4% and molar activities between 33 and 114 GBq/µmol. Specific binding of [18F]3 to CB2 was demonstrated by in vitro autoradiography and in vivo PET experiments using the CB2 ligand GW-405 833. Metabolite analysis revealed only intact [18F]3 in the rat brain. [18F]3 detected CB2 upregulation in human amyotrophic lateral sclerosis spinal cord tissue and may thus become a candidate for diagnostic use in humans.


Assuntos
Encéfalo/metabolismo , Radioisótopos de Flúor/metabolismo , Neuroimagem/métodos , Tomografia por Emissão de Pósitrons/métodos , Piridinas/química , Compostos Radiofarmacêuticos/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Animais , Encéfalo/diagnóstico por imagem , AMP Cíclico/metabolismo , Radioisótopos de Flúor/química , Hepatócitos/metabolismo , Humanos , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Conformação Proteica , Radioquímica , Compostos Radiofarmacêuticos/química , Ratos , Ratos Wistar , Receptor CB2 de Canabinoide/química , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...