RESUMEN
Based on the theoretical understanding of the in vivo lysosomotropism, by adjusting the pk(a) of basic nitrogen containing cathepsin S inhibitors, a set of compounds with pk(a) 6-8 were identified to have excellent cell based Lip10 activity, yet avoiding undesired sequestration in spleen.
Asunto(s)
Catepsinas/antagonistas & inhibidores , Nitrógeno/química , Inhibidores de Proteasas/química , Piridinas/química , Animales , Catepsinas/metabolismo , Ratones , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacocinética , Piridinas/síntesis química , Piridinas/farmacocinética , Ratas , Ratas Sprague-DawleyRESUMEN
Using computer aided modelling studies, a new extended P2/S2 interaction was identified. This extended region can accommodate a variety of functional groups, such as aryls and basic amines. It was discovered that the N3 nitrogen of the pyrimidine-2-carbonitrile is critical for its cathepsin cysteine protease inhibition. N1 nitrogen also contributes to the inhibitory activity, but to a very limited degree. An 'in situ double activation' mechanism was proposed to explain these results.
Asunto(s)
Catepsinas/antagonistas & inhibidores , Nitrilos/química , Inhibidores de Proteasas/química , Pirimidinas/química , Sitios de Unión , Catepsinas/metabolismo , Simulación por Computador , Humanos , Modelos Moleculares , Nitrilos/síntesis química , Nitrilos/farmacología , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacologíaRESUMEN
Starting from previously disclosed equally potent cathepsin K and S inhibitor 4-propyl-6-(3-trifluoromethylphenyl)pyrimidine-2-carbonitrile 1, a novel 2-phenyl-9H-purine-6-carbonitrile scaffold was identified to provide potent and selective cathepsin S inhibitors.
Asunto(s)
Catepsinas/antagonistas & inhibidores , Nitrilos/química , Inhibidores de Proteasas/química , Purinas/química , Dominio Catalítico , Catepsina K/antagonistas & inhibidores , Catepsina K/metabolismo , Catepsinas/metabolismo , Línea Celular , Simulación por Computador , Humanos , Nitrilos/síntesis química , Nitrilos/farmacología , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Purinas/síntesis química , Purinas/farmacología , Pirimidinas/químicaRESUMEN
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.
Asunto(s)
Catepsinas/antagonistas & inhibidores , Nitrilos/química , Inhibidores de Proteasas/química , Piridinas/química , Animales , Sitios de Unión , Catepsinas/metabolismo , Línea Celular , Cristalografía por Rayos X , Humanos , Ratones , Nitrilos/síntesis química , Nitrilos/farmacocinética , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacocinética , Piridinas/síntesis química , Piridinas/farmacocinética , Relación Estructura-ActividadRESUMEN
A study into the effect of reaction variables on the quaternization of REM resin-bound tertiary amines was undertaken. The influence of resin matrix, solvent, reaction time, temperature, and amount of quaternization agent on the outcome of reaction was evaluated by reaction monitoring using (19)F NMR. The highest yields of tertiary amine products were seen when DMSO was used as reaction solvent in conjunction with a reaction time of 18 h at room temperature. The use of heating for extended reaction times tended to depress yields, indicating product cleavage during quaternization. Quaternization on PS-DVB resin was found to be more robust than reaction on PS-PEG matrices where yields were generally considerably lower than the observed conversions. DMSO was the most efficient reaction solvent for both resins despite poor swelling of the quaternization starting material.
Asunto(s)
Aminas/síntesis química , Técnicas Químicas Combinatorias/métodos , Aminación , Flúor , Espectroscopía de Resonancia Magnética , Resinas Sintéticas/química , Resinas Sintéticas/normas , Solventes/farmacología , Temperatura , Factores de TiempoRESUMEN
A series of carboxyl-containing cyclophanes have been designed and synthesised as chemical chelators (or host molecules) of cationic muscle relaxant drugs (or guest molecules). Three of these cyclophane derivatives, 1-3, have been shown by NMR to form 1:1 complexes with the muscle relaxants pancuronium, and gallamine, in D(2)O, with association constants up to 10(4) M(-1). When tested in an in vitro chick biventer muscle preparation, the cyclophanes reversed the neuromuscular block induced by pancuronium and gallamine, with having the most effective reversal against pancuronium (EC(50) 40 microM.