RESUMEN
Heteroarylalanine derivatives 4 were designed as potential inhibitors of neutral endopeptidase (NEP EC 3.4.24.11). Selectivity over other zinc metalloproteinases was explored through occupation of the S2' subsite within NEP. Structural optimisation led to the identification of 5-phenyl oxazole 4f, a potent and selective NEP inhibitor. A crystal structure of the inhibitor bound complex is reported.
Asunto(s)
Ácidos/síntesis química , Alanina/síntesis química , Neprilisina/antagonistas & inhibidores , Oxazoles/química , Oxazoles/farmacología , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Ácidos/química , Ácidos/farmacología , Alanina/química , Alanina/farmacología , Cristalografía por Rayos X , Activación Enzimática/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteasas/químicaRESUMEN
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.
Asunto(s)
4-Aminopiridina/análogos & derivados , Química Farmacéutica/métodos , Canales de Potasio Éter-A-Go-Go/química , Receptores Opioides delta/agonistas , 4-Aminopiridina/síntesis química , 4-Aminopiridina/farmacología , Analgésicos Opioides/farmacología , Animales , Línea Celular , Técnicas Químicas Combinatorias , Diseño de Fármacos , Canal de Potasio ERG1 , Electromiografía/métodos , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , Modelos Químicos , Ratas , Receptores Opioides delta/química , Relación Estructura-ActividadRESUMEN
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.
