RESUMEN
N-Hydroxy-2-arylisoindoline-4-carboxamides are potent and selective inhibitors of HDAC11. The discovery, synthesis, and structure activity relationships of this novel series of inhibitors are reported. An advanced analog (FT895) displays promising cellular activity and pharmacokinetic properties that make it a useful tool to study the biology of HDAC11 and its potential use as a therapeutic target for oncology and inflammation indications.
Asunto(s)
Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Histona Desacetilasas/metabolismo , Isoindoles/farmacología , Animales , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Isoindoles/síntesis química , Isoindoles/química , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Estructura Molecular , Proteínas Recombinantes/metabolismo , Relación Estructura-ActividadRESUMEN
Design, synthesis and structure-activity relationship of a series of biphenylsulfonamido-3-methylbutanoic acid based aggrecanase-1 inhibitors are described. In addition to robust aggrecanase-1 inhibition, these compounds also exhibit potent MMP-13 activity. In cell-based cartilage explants assay compound 48 produced 87% inhibition of proteoglycan degradation at 10 µg/mL. Good pharmacokinetic properties were demonstrated by 46 with a half-life of 6h and bioavailability of 23%.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Proteínas ADAM/metabolismo , Compuestos de Bifenilo/farmacología , Procolágeno N-Endopeptidasa/antagonistas & inhibidores , Procolágeno N-Endopeptidasa/metabolismo , Inhibidores de Proteasas/farmacología , Sulfonamidas/farmacología , Proteína ADAMTS4 , Animales , Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacocinética , Diseño de Fármacos , Humanos , Masculino , Metaloproteinasa 13 de la Matriz/metabolismo , Modelos Moleculares , Osteoartritis/tratamiento farmacológico , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacocinética , Proteoglicanos/metabolismo , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacocinéticaRESUMEN
Potent 3,4-disubstituted benzofuran P1' MMP-13 inhibitors have been prepared. Selectivity over MMP-2 was achieved through a substituent at the C4 position of the benzofuran P1' moiety of the molecule. By replacing a backbone benzene with a pyridine and valine with threonine, compounds (e.g., 44) with greatly reduced plasma protein binding were also obtained.
Asunto(s)
Benzofuranos/química , Inhibidores de la Metaloproteinasa de la Matriz , Inhibidores de Proteasas/química , Animales , Benzofuranos/síntesis química , Benzofuranos/farmacología , Metaloproteinasa 13 de la Matriz/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Unión Proteica , Conejos , Albúmina Sérica/química , Relación Estructura-ActividadRESUMEN
Through fragment-based drug design focused on engaging the active site of IRAK4 and leveraging three-dimensional topology in a ligand-efficient manner, a micromolar hit identified from a screen of a Pfizer fragment library was optimized to afford IRAK4 inhibitors with nanomolar potency in cellular assays. The medicinal chemistry effort featured the judicious placement of lipophilicity, informed by co-crystal structures with IRAK4 and optimization of ADME properties to deliver clinical candidate PF-06650833 (compound 40). This compound displays a 5-unit increase in lipophilic efficiency from the fragment hit, excellent kinase selectivity, and pharmacokinetic properties suitable for oral administration.
Asunto(s)
Descubrimiento de Drogas , Quinasas Asociadas a Receptores de Interleucina-1/antagonistas & inhibidores , Isoquinolinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Administración Oral , Relación Dosis-Respuesta a Droga , Humanos , Quinasas Asociadas a Receptores de Interleucina-1/metabolismo , Isoquinolinas/administración & dosificación , Isoquinolinas/química , Lactamas , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/química , Relación Estructura-ActividadRESUMEN
The synthesis and structure-activity studies of a series of quinoline-3-carbonitriles as inhibitors of Tpl2 kinase are described. Potent inhibitors of Tpl2 kinase with selectivity against a panel of selected kinases in enzymatic assays and specificity in cell-based phosphorylation assays in LPS-treated human monocytes were identified. Selected inhibitors with moderate activity in human whole blood assay effectively inhibited LPS/D-Gal induced TNFalpha release when administered intraperitoneally in mice.
Asunto(s)
Artritis Reumatoide/metabolismo , Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Nitrilos/química , Nitrilos/farmacología , Quinolinas/química , Factor de Necrosis Tumoral alfa/biosíntesis , Artritis Reumatoide/tratamiento farmacológico , Reactivos de Enlaces Cruzados/química , Humanos , Imidazoles/química , Quinasas Quinasa Quinasa PAM/metabolismo , Estructura Molecular , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Nitrilos/síntesis química , Relación Estructura-ActividadRESUMEN
Aggrecanases are recently discovered enzymes that cleave aggrecan, a key component of cartilage. Aggrecanase inhibitors may provide a unique means to halt the progression of cartilage destruction in osteoarthritis. The synthesis and evaluation of biphenylsulfonamidocarboxylic acid inhibitors of aggrecanase-1 are reported. Compound 24 demonstrated 89% inhibition of proteoglycan degradation at 10 microg/mL and has an oral bioavailability in rat of 35%.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Compuestos de Bifenilo/química , Ácidos Carboxílicos , Inhibidores Enzimáticos , Procolágeno N-Endopeptidasa/antagonistas & inhibidores , Sulfonamidas/química , Proteína ADAMTS4 , Administración Oral , Animales , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacología , Colagenasas/metabolismo , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Metaloproteinasa 13 de la Matriz , Inhibidores de la Metaloproteinasa de la Matriz , Modelos Moleculares , Estructura Molecular , Proteoglicanos/efectos de los fármacos , Proteoglicanos/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
Modification of alpha-biphenylsulfonamidocarboxylic acids led to potent and selective MMP-13 inhibitors. Compound 16 showed 100% oral bioavailability in rats and demonstrated >50% inhibition of bovine cartilage degradation at 10 ng/mL.
Asunto(s)
Colagenasas/metabolismo , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/farmacocinética , Inhibidores de la Metaloproteinasa de la Matriz , Osteoartritis/tratamiento farmacológico , Administración Oral , Animales , Benzofuranos/síntesis química , Benzofuranos/química , Colagenasas/química , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Concentración 50 Inhibidora , Metaloproteinasa 13 de la Matriz , Modelos Moleculares , Estructura Molecular , Ratas , Especificidad por SustratoRESUMEN
The structure-based design and synthesis of a series of novel biphenyl sulfonamide carboxylic acids as potent MMP-13 inhibitors with selectivity over MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-14, Aggrecanase 1, and TACE are described.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores de la Metaloproteinasa de la Matriz , Aminación , Benzofuranos/química , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacología , Colagenasas/metabolismo , Inhibidores Enzimáticos/química , Concentración 50 Inhibidora , Metaloproteinasa 13 de la Matriz , Estructura Molecular , Relación Estructura-Actividad , Azufre/químicaRESUMEN
The synthesis and structure-activity studies of a series of 6-substituted-4-anilino-[1,7]-naphthyridine-3-carbonitriles as inhibitors of Tpl2 kinase are described. The early exploratory work described here may lead to the discovery of compounds with significant therapeutic potential for treating rheumatoid arthritis and other inflammatory diseases.