RESUMO
We have previously reported a series of anilinoquinazoline derivatives as potent and selective biochemical inhibitors of the RET kinase domain. However, these derivatives displayed diminished cellular potency. Herein we describe further optimisation of the series through modification of their physicochemical properties, delivering improvements in cell potency. However, whilst cellular selectivity against key targets could be maintained, combining cell potency and acceptable pharmacokinetics proved challenging.
Assuntos
Compostos de Anilina/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Quinazolinas/farmacologia , Compostos de Anilina/síntese química , Compostos de Anilina/química , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-ret/metabolismo , Quinazolinas/síntese química , Quinazolinas/química , Relação Estrutura-AtividadeRESUMO
Starting from compound 1, we utilized biostructural data to successfully evolve an existing series into a new chemotype with a promising overall profile, exemplified by 19.
Assuntos
Desenho de Fármacos , Indanos/química , Indanos/farmacologia , Receptores de AMPA/metabolismo , Sulfonamidas/química , Sulfonamidas/farmacologia , Regulação Alostérica , Animais , Linhagem Celular , Cristalografia por Raios X , Humanos , Indanos/metabolismo , Indanos/farmacocinética , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/metabolismo , Pirazóis/química , Pirazóis/metabolismo , Pirazóis/farmacocinética , Pirazóis/farmacologia , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Sulfonamidas/metabolismo , Sulfonamidas/farmacocinéticaRESUMO
Starting from an HTS derived hit 1, application of biostructural data facilitated rapid optimization to lead 22, a novel AMPA receptor modulator. This is the first demonstration of how structure based drug design can be exploited in an optimization program for a glutamate receptor.
Assuntos
Indazóis/química , Receptores de AMPA/química , Tiofenos/química , Regulação Alostérica , Animais , Sítios de Ligação , Cristalografia por Raios X , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Ensaios de Triagem em Larga Escala , Humanos , Indazóis/síntese química , Indazóis/farmacologia , Microssomos/metabolismo , Estrutura Terciária de Proteína , Ratos , Receptores de AMPA/metabolismo , Tiofenos/síntese química , Tiofenos/farmacologiaRESUMO
Starting from lead compound 1, we demonstrate how X-ray structural data can be used to understand SAR and expediently optimize bioavailability in a novel series of AMPA receptor modulators, furnishing 5 with improved bioavailability and robust in vivo activity.
Assuntos
Aminas/química , Aminas/farmacologia , Desenho de Fármacos , Pirazóis/química , Pirazóis/farmacologia , Receptores de AMPA/metabolismo , Regulação Alostérica , Aminas/síntese química , Aminas/farmacocinética , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Humanos , Modelos Moleculares , Pirazóis/síntese química , Pirazóis/farmacocinética , Ratos , Ratos Wistar , Receptores de AMPA/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Deregulation of the receptor tyrosine kinase RET has been implicated in medullary thyroid cancer, a small percentage of lung adenocarcinomas, endocrine-resistant breast cancer and pancreatic cancer. There are several clinically approved multi-kinase inhibitors that target RET as a secondary pharmacology but additional activities, most notably inhibition of KDR, lead to dose-limiting toxicities. There is, therefore, a clinical need for more specific RET kinase inhibitors. Herein we report our efforts towards identifying a potent and selective RET inhibitor using vandetanib 1 as the starting point for structure-based drug design. Phenolic anilinoquinazolines exemplified by 6 showed improved affinities towards RET but, unsurprisingly, suffered from high metabolic clearance. Efforts to mitigate the metabolic liability of the phenol led to the discovery that a flanking substituent not only improved the hepatocyte stability, but could also impart a significant gain in selectivity. This culminated in the identification of 36; a potent RET inhibitor with much improved selectivity against KDR.
Assuntos
Piperidinas/química , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Quinazolinas/química , Quinazolinas/farmacologia , Animais , Linhagem Celular , Desenho de Fármacos , Humanos , Camundongos , Simulação de Acoplamento Molecular , Piperidinas/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Proto-Oncogênicas c-ret/metabolismo , Quinazolinas/farmacocinéticaRESUMO
Novel derivatives of the steroid DHEA 1, a known uncompetitive inhibitor of G6PD, were designed, synthesized, and tested for their ability to inhibit this dehydrogenase enzyme. Several compounds with approximately 10-fold improved potency in an enzyme assay were identified, and this improved activity translated to efficacy in a cellular assay. The SAR for steroid inhibition of G6PD has been substantially developed; the 3ß-alcohol can be replaced with 3ß-H-bond donors such as sulfamide, sulfonamide, urea, and carbamate. Improved potency was achieved by replacing the androstane nucleus with a pregnane nucleus, provided a ketone at C-20 is present. For pregnan-20-ones incorporation of a 21-hydroxyl group is often beneficial. The novel compounds generally have good physicochemical properties and satisfactory in vitro DMPK parameters. These derivatives may be useful for examining the role of G6PD inhibition in cells and will assist the future design of more potent steroid inhibitors with potential therapeutic utility.