RESUMO
Novel, low brain penetrant, orally bioavailable CB1 receptor agonists were designed starting from a mature lead series of potent brain penetrant CB1 receptor agonists. Increasing the calculated polar surface area was found to be a good strategy for reducing brain penetration whilst retaining drug-like properties. This in silico approach led to the discovery of LBP1, an orally bioavailable, low brain penetrant CB1 receptor agonist with robust activity in rodent models of neuropathic pain and a good preclinical therapeutic profile, which was selected for clinical development.
Assuntos
Desenho de Fármacos , Indóis/síntese química , Neuralgia/tratamento farmacológico , Oxidiazóis/síntese química , Receptor CB1 de Canabinoide/agonistas , Animais , Encéfalo/irrigação sanguínea , Encéfalo/metabolismo , Células CACO-2 , Humanos , Indóis/química , Indóis/farmacocinética , Camundongos , Oxidiazóis/química , Oxidiazóis/farmacocinética , RatosRESUMO
6-Phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile analogues were identified as potent and selective cathepsin S inhibitor against both purified enzyme and in human JY cell based cellular assays. This core has a very stable thio-trapping nitrile war-head in comparison with the well reported pyrimidine-2-carbonitrile cysteine cathepsin inhibitors. Compound 47 is also very potent in in vivo mouse spleenic Lip10 accumulation assays.
Assuntos
Catepsinas/antagonistas & inibidores , Nitrilas/química , Inibidores de Proteases/química , Piridinas/química , Animais , Sítios de Ligação , Catepsinas/metabolismo , Linhagem Celular , Cristalografia por Raios X , Humanos , Camundongos , Nitrilas/síntese química , Nitrilas/farmacocinética , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacocinética , Piridinas/síntese química , Piridinas/farmacocinética , Relação Estrutura-AtividadeRESUMO
A number of water soluble bis-amino-2,6-dimethoxyphenyl ester derivatives were found to exhibit improved anaesthetic activity in mice relative to propofol 1. Of the analogues disclosed, 44 was further profiled in rodents and found to be a superior agent to propofol for the induction and maintenance of anaesthesia.
Assuntos
Anestésicos Intravenosos/química , Anestésicos Intravenosos/farmacologia , Ésteres/química , Ésteres/farmacologia , Fenóis/química , Fenóis/farmacologia , Anestésicos Intravenosos/síntese química , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Eletroencefalografia/efeitos dos fármacos , Ésteres/síntese química , Infusões Intravenosas/métodos , Masculino , Camundongos , Camundongos Mutantes , Fenóis/síntese química , Propofol/farmacologia , Ratos , Ratos Wistar , Receptores de GABA-A/efeitos dos fármacos , Solubilidade , Relação Estrutura-Atividade , Água/químicaRESUMO
A novel series of alpha-amino-acid phenolic ester derivatives containing sulphide, sulphoxide, sulphone, ester and amide side chains were prepared and shown to display potent intravenous anaesthetic activity.
