RESUMO
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
1-isoquinolinylguanidines were previously disclosed as potent and selective inhibitors of urokinase-type plasminogen activator (uPA). Further investigation of this template has revealed that incorporation of a 7-sulfonamide group furnishes a new series of potent and highly selective uPA inhibitors. Potency and selectivity can be achieved with sulfonamides derived from a variety of amines and is further enhanced by the incorporation of sulfonamides derived from amino acids. The binding mode of these 1-isoquinolinylguanidines has been investigated by X-ray cocrystallization studies. uPA inhibitor 26 was selected for further evaluation based on its excellent enzyme potency (Ki 10 nM) and selectivity profile (4000-fold versus tPA and 2700-fold versus plasmin). In vitro, compound 26 is able to inhibit exogenous uPA in human chronic wound fluid (IC50=0.89 microM). In vivo, in a porcine acute excisional wound model, following topical delivery, compound 26 is able to penetrate into pig wounds and inhibit exogenous uPA activity with no adverse effect on wound healing parameters. On the basis of this profile, compound 26 (UK-371,804) was selected as a candidate for further preclinical evaluation for the treatment of chronic dermal ulcers.
Assuntos
Antiulcerosos/síntese química , Guanidinas/síntese química , Quinolinas/síntese química , Sulfonamidas/síntese química , Ativador de Plasminogênio Tipo Uroquinase/antagonistas & inibidores , Doença Aguda , Animais , Antiulcerosos/química , Antiulcerosos/farmacologia , Sítios de Ligação , Doença Crônica , Cristalografia por Raios X , Guanidinas/química , Guanidinas/farmacologia , Humanos , Técnicas In Vitro , Modelos Moleculares , Ligação Proteica , Quinolinas/química , Quinolinas/farmacologia , Pele/lesões , Dermatopatias/enzimologia , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , Suínos , Úlcera/enzimologia , Ativador de Plasminogênio Tipo Uroquinase/química , Cicatrização/efeitos dos fármacosRESUMO
The identification of 2-pyridinylguanidines (e.g., 27 and 28) as selective inhibitors of urokinase-type plasminogen activator (uPA) is described. The X-ray crystal structure of 27 has been determined, and modelling has been used to predict binding in the enzyme active site.
