RESUMEN
Two structurally distinct series of novel, MAPK-activated kinase-2 prevention of activation inhibitors have been discovered by high throughput screening. Preliminary structure-activity relationship (SAR) studies revealed substructural features that influence the selective inhibition of the activation by p38α of the downstream kinase MK2 in preference to an alternative substrate, MSK1. Enzyme kinetics, surface plasmon resonance (SPR), 2D protein NMR, and X-ray crystallography were used to determine the binding mode and the molecular mechanism of action. The compounds bind competitively to the ATP binding site of p38α but unexpectedly with higher affinity in the p38α-MK2 complex compared with p38α alone. This observation is hypothesized to be the origin of the substrate selectivity. The two lead series identified are suitable for further investigation for their potential to treat chronic inflammatory diseases with improved tolerability over previously studied p38α inhibitors.
Asunto(s)
MAP Quinasa Quinasa 2/antagonistas & inhibidores , MAP Quinasa Quinasa 2/química , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Adenosina Trifosfato/química , Adenosina Trifosfato/metabolismo , Unión Competitiva , Células Cultivadas , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Activación Enzimática/efectos de los fármacos , Humanos , Cinética , MAP Quinasa Quinasa 2/metabolismo , Espectroscopía de Resonancia Magnética , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 14 Activada por Mitógenos/química , Proteína Quinasa 14 Activada por Mitógenos/metabolismo , Modelos Químicos , Modelos Moleculares , Estructura Molecular , Fosforilación/efectos de los fármacos , Unión Proteica , Inhibidores de Proteínas Quinasas/metabolismo , Estructura Terciaria de Proteína , Proteínas Quinasas S6 Ribosómicas 90-kDa/antagonistas & inhibidores , Proteínas Quinasas S6 Ribosómicas 90-kDa/química , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Relación Estructura-Actividad , Especificidad por Sustrato , Resonancia por Plasmón de SuperficieRESUMEN
Removal of the basic piperazine nitrogen atom, introduction of a solubilising end group and partial reduction of the triazolopyridazine moiety in the previously-described lead androgen receptor downregulator 6-[4-(4-cyanobenzyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (1) addressed hERG and physical property issues, and led to clinical candidate 6-(4-{4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (12), designated AZD3514, that is being evaluated in a Phase I clinical trial in patients with castrate-resistant prostate cancer.
Asunto(s)
Regulación hacia Abajo/efectos de los fármacos , Descubrimiento de Drogas , Neoplasias de la Próstata/tratamiento farmacológico , Piridazinas/farmacología , Receptores Androgénicos/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Masculino , Estructura Molecular , Neoplasias de la Próstata/patología , Piridazinas/síntesis química , Piridazinas/química , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-ActividadRESUMEN
A series of potent Cathepsin L inhibitors with good selectivity with respect to other cysteine Cathepsins is described and SAR is discussed with reference to the crystal structure of a protein-ligand complex.
Asunto(s)
Catepsina L/antagonistas & inhibidores , Catepsina L/química , Nitrilos/síntesis química , Animales , Cartílago Articular/patología , Catálisis , Química Farmacéutica/métodos , Cristalografía por Rayos X/métodos , Diseño de Fármacos , Humanos , Ligandos , Ratones , Ratones Transgénicos , Nitrilos/química , Nitrilos/farmacología , Péptidos/síntesis química , Péptidos/farmacología , Proteínas/química , Relación Estructura-ActividadRESUMEN
A novel p38 MAP kinase inhibitor structural class was discovered through selectivity screening. The rational analogue design, synthesis and structure-activity relationship of this series of bis-amide inhibitors is reported. The inhibition in vitro of human p38alpha enzyme activity and lipopolysaccharide-induced tumour necrosis factor-alpha release is described for the series. The activity in vivo and pharmacokinetic properties are exemplified for the more potent analogues.
