RESUMEN
The optimisation of the azanaphthyridine series of Spleen Tyrosine Kinase inhibitors is described. The medicinal chemistry strategy was focused on optimising the human whole blood activity whilst achieving a sufficient margin over hERG activity. A good pharmacokinetic profile was achieved by modification of the pKa. Morpholine compound 32 is a potent SYK inhibitor showing moderate selectivity, good oral bioavailability and good efficacy in the rat Arthus model but demonstrated a genotoxic potential in the Ames assay.
Asunto(s)
Naftiridinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Administración Oral , Animales , Disponibilidad Biológica , Cristalografía por Rayos X , Humanos , Pruebas de Mutagenicidad , Naftiridinas/administración & dosificación , Naftiridinas/farmacocinética , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
The lead optimisation of the diaminopyrimidine carboxamide series of spleen tyrosine kinase inhibitors is described. The medicinal chemistry strategy was focused on optimising the human whole blood activity whilst achieving a sufficient margin over liability kinases and hERG activity. GSK143 is a potent and highly selective SYK inhibitor showing good efficacy in the rat Arthus model.
Asunto(s)
Compuestos de Anilina/química , Compuestos de Anilina/uso terapéutico , Antiinflamatorios/química , Antiinflamatorios/uso terapéutico , Reacción de Arthus/tratamiento farmacológico , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirimidinas/química , Pirimidinas/uso terapéutico , Administración Oral , Compuestos de Anilina/farmacología , Animales , Antiinflamatorios/farmacología , Cristalografía por Rayos X , Descubrimiento de Drogas , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Modelos Moleculares , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/metabolismo , Pirimidinas/farmacología , Ratas , Relación Estructura-Actividad , Quinasa SykRESUMEN
Herein, a series of 2,3-dihydrobenzofurans have been developed as highly potent bromo and extra-terminal domain (BET) inhibitors with 1000-fold selectivity for the second bromodomain (BD2) over the first bromodomain (BD1). Investment in the development of two orthogonal synthetic routes delivered inhibitors that were potent and selective but had raised in vitro clearance and suboptimal solubility. Insertion of a quaternary center into the 2,3-dihydrobenzofuran core blocked a key site of metabolism and improved the solubility. This led to the development of inhibitor 71 (GSK852): a potent, 1000-fold-selective, highly soluble compound with good in vivo rat and dog pharmacokinetics.
Asunto(s)
Benzofuranos/farmacología , Proteínas/antagonistas & inhibidores , Benzofuranos/síntesis química , Benzofuranos/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Proteínas/metabolismo , Solubilidad , Relación Estructura-ActividadRESUMEN
The two tandem bromodomains of the BET (bromodomain and extraterminal domain) proteins enable chromatin binding to facilitate transcription. Drugs that inhibit both bromodomains equally have shown efficacy in certain malignant and inflammatory conditions. To explore the individual functional contributions of the first (BD1) and second (BD2) bromodomains in biology and therapy, we developed selective BD1 and BD2 inhibitors. We found that steady-state gene expression primarily requires BD1, whereas the rapid increase of gene expression induced by inflammatory stimuli requires both BD1 and BD2 of all BET proteins. BD1 inhibitors phenocopied the effects of pan-BET inhibitors in cancer models, whereas BD2 inhibitors were predominantly effective in models of inflammatory and autoimmune disease. These insights into the differential requirement of BD1 and BD2 for the maintenance and induction of gene expression may guide future BET-targeted therapies.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Antineoplásicos/farmacología , Proteínas de Ciclo Celular/antagonistas & inhibidores , Histona Acetiltransferasas/antagonistas & inhibidores , Factores Inmunológicos/farmacología , Terapia Molecular Dirigida , Factores de Transcripción/antagonistas & inhibidores , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/uso terapéutico , Antineoplásicos/uso terapéutico , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/genética , Descubrimiento de Drogas , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HEK293 , Histona Acetiltransferasas/química , Histona Acetiltransferasas/genética , Humanos , Enfermedades del Sistema Inmune/tratamiento farmacológico , Factores Inmunológicos/química , Factores Inmunológicos/uso terapéutico , Inflamación/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Dominios Proteicos/efectos de los fármacos , Factores de Transcripción/química , Factores de Transcripción/genéticaRESUMEN
Crystallography-driven optimisation of a lead derived from similarity searching of the GSK compound collection resulted in the discovery of a series of quinoline derivatives that were highly potent and selective inhibitors of PDE4 with a good pharmacokinetic profile in the rat. Quinolines 43 and 48 have potential as oral medicines for the treatment of COPD.
Asunto(s)
Inhibidores de Fosfodiesterasa 4 , Inhibidores de Fosfodiesterasa/administración & dosificación , Inhibidores de Fosfodiesterasa/química , Quinolinas/administración & dosificación , Quinolinas/química , Administración Oral , Animales , Bovinos , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Humanos , Masculino , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Following the discovery of cell penetrant pyridine-4-carboxylate inhibitors of the KDM4 (JMJD2) and KDM5 (JARID1) families of histone lysine demethylases (e.g., 1), further optimization led to the identification of non-carboxylate inhibitors derived from pyrido[3,4-d]pyrimidin-4(3H)-one. A number of exemplars such as compound 41 possess interesting activity profiles in KDM4C and KDM5C biochemical and target-specific, cellular mechanistic assays.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Histona Demetilasas/antagonistas & inhibidores , Histona Demetilasas con Dominio de Jumonji/antagonistas & inhibidores , Pirimidinonas/química , Pirimidinonas/farmacología , Línea Celular , Permeabilidad de la Membrana Celular , Cristalografía por Rayos X , Inhibidores Enzimáticos/farmacocinética , Histona Demetilasas/química , Histona Demetilasas/metabolismo , Humanos , Histona Demetilasas con Dominio de Jumonji/química , Histona Demetilasas con Dominio de Jumonji/metabolismo , Modelos Moleculares , Simulación del Acoplamiento Molecular , Pirimidinonas/farmacocinética , Relación Estructura-ActividadRESUMEN
Optimization of KDM6B (JMJD3) HTS hit 12 led to the identification of 3-((furan-2-ylmethyl)amino)pyridine-4-carboxylic acid 34 and 3-(((3-methylthiophen-2-yl)methyl)amino)pyridine-4-carboxylic acid 39 that are inhibitors of the KDM4 (JMJD2) family of histone lysine demethylases. Compounds 34 and 39 possess activity, IC50 ≤ 100 nM, in KDM4 family biochemical (RFMS) assays with ≥ 50-fold selectivity against KDM6B and activity in a mechanistic KDM4C cell imaging assay (IC50 = 6-8 µM). Compounds 34 and 39 are also potent inhibitors of KDM5C (JARID1C) (RFMS IC50 = 100-125 nM).