RESUMO
A series of benzimidazole CB(2) receptor agonists were prepared and their properties investigated. Optimisation of the three benzimidazole substituents led to the identification of compound 23, a potent CB(2) full agonist (EC(50) 2.7nM) with excellent selectivity over the CB(1) receptor (>3000-fold). Compound 23 demonstrated good CNS penetration in rat. Further optimisation led to the identification of compound 34 with improved selectivity over hERG and excellent CNS penetration in rat.
Assuntos
Analgésicos/química , Benzimidazóis/química , Sistema Nervoso Central/metabolismo , Receptor CB2 de Canabinoide/agonistas , Analgésicos/síntese química , Analgésicos/farmacocinética , Animais , Benzimidazóis/síntese química , Benzimidazóis/farmacocinética , Microssomos Hepáticos/metabolismo , Ratos , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Relação Estrutura-AtividadeRESUMO
A number of libraries were produced to explore the potential of 2,4-diaminopyridine lead 1. The resulting diaminopyridines proved to be potent and selective delta-opioid receptor agonists. Several rounds of lead optimisation using library chemistry identified compound 17 which went on to show efficacy in an electromyography model of neuropathic pain. The structure-activity relationship of the series against the hERG ion channel proved to be a key selectivity hurdle for the series.
Assuntos
4-Aminopiridina/análogos & derivados , Química Farmacêutica/métodos , Canais de Potássio Éter-A-Go-Go/química , Receptores Opioides delta/agonistas , 4-Aminopiridina/síntese química , 4-Aminopiridina/farmacologia , Analgésicos Opioides/farmacologia , Animais , Linhagem Celular , Técnicas de Química Combinatória , Desenho de Fármacos , Canal de Potássio ERG1 , Eletromiografia/métodos , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Modelos Químicos , Ratos , Receptores Opioides delta/química , Relação Estrutura-AtividadeRESUMO
A series of novel mGluR1 antagonists have been prepared. Incorporation of fragments derived from weak lead matter into a library led to enhanced potency in a new chemical series. A chemistry driven second library iteration, covering a greatly enhanced area of chemical space, maintained good potency and introduced metabolic stability.
