RESUMO
This paper describes our recent efforts to design and synthesise potent and selective PDE5 inhibitors and the use of in vitro predictors of clearance, absorption and permeability to maximise the potential for dose-proportional pharmacokinetics and good oral bioavailability in man. Optimisation of the preclinical profile resulted in the identification of UK-369003 (19a) and its nomination as a clinical candidate. The clinical pharmacokinetic and safety profile has enabled us to progress the compound to test its efficacy in patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) and a paper describing its efficacy has recently been published.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/química , Inibidores da Fosfodiesterase 5/química , Inibidores da Fosfodiesterase 5/farmacocinética , Pirimidinonas/química , Pirimidinonas/farmacocinética , Sulfonamidas/química , Sulfonamidas/farmacocinética , Administração Oral , Disponibilidade Biológica , Linhagem Celular , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Humanos , Sintomas do Trato Urinário Inferior/tratamento farmacológico , Sintomas do Trato Urinário Inferior/etiologia , Masculino , Inibidores da Fosfodiesterase 5/farmacologia , Hiperplasia Prostática/complicações , Pirimidinonas/farmacologia , Sulfonamidas/farmacologiaRESUMO
The SAR of a series of novel pyrido[3,4-d]pyramid-4-ylamine mGluR1 antagonists is described. The multiple of the unbound K(i) in cerebrospinal fluid necessary to give morphine like analgesic effects in an electromyograph pinch model in rodents is determined and the effect of structure on CNS penetration examined.
Assuntos
Antagonistas de Aminoácidos Excitatórios/síntese química , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Animais , Eletromiografia/métodos , Antagonistas de Aminoácidos Excitatórios/química , Antagonistas de Aminoácidos Excitatórios/farmacologia , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Ratos , Receptores de Glutamato Metabotrópico/fisiologia , Relação Estrutura-AtividadeRESUMO
Voltage-gated sodium channels, in particular Nav1.8, can be targeted for the treatment of neuropathic and inflammatory pain. Herein, we described the optimization of Nav1.8 modulator series to deliver subtype selective, state, and use-dependent chemical matter that is efficacious in preclinical models of neuropathic and inflammatory pain.
RESUMO
A series of zwitterionic delta-opioid agonists, with targeted physicochemistry, as a strategy to limit potential for CNS exposure, were prepared. These agents were found to possess exquisite potency and selectivity over mu and kappa-opiate activity. Furthermore, analogue 3a was found to display restricted CNS exposure, as evidenced by its inactivity in a rodent hyperlocomotion assay of central opiate activity. Dog pharmacokinetic studies on 3a indicated encouraging oral bioavailability.
Assuntos
Indóis/farmacologia , Isoquinolinas/farmacologia , Receptores Opioides delta/agonistas , Animais , Cães , Desenho de Fármacos , Indóis/administração & dosagem , Indóis/síntese química , Isoquinolinas/administração & dosagem , Isoquinolinas/síntese química , Camundongos , Conformação Molecular , Peso Molecular , Relação Estrutura-AtividadeRESUMO
The SAR of a series of beta-carboline derived type 5 phosphodiesterase inhibitors has been explored and we have discovered compounds with excellent levels of PDE5 potency and selectivity over PDE6. However, the series exhibits low levels of selectivity over PDE11, a phosphodiesterase with unknown function.