RESUMEN
Facilitating activation, or delaying inactivation, of the native Kv7 channel reduces neuronal excitability, which may be beneficial in controlling spontaneous electrical activity during epileptic seizures. In an effort to identify a compound with such properties, the structure-activity relationship (SAR) and in vitro ADME for a series of heterocyclic Kv7.2-7.5 channel openers was explored. PF-05020182 (2) demonstrated suitable properties for further testing in vivo where it dose-dependently decreased the number of animals exhibiting full tonic extension convulsions in response to corneal stimulation in the maximal electroshock (MES) assay. In addition, PF-05020182 (2) significantly inhibited convulsions in the MES assay at doses tested, consistent with in vitro activity measure. The physiochemical properties, in vitro and in vivo activities of PF-05020182 (2) support further development as an adjunctive treatment of refractory epilepsy.
Asunto(s)
Descubrimiento de Drogas , Epilepsia/tratamiento farmacológico , Activación del Canal Iónico/efectos de los fármacos , Canal de Potasio KCNQ2/metabolismo , Piperidinas/farmacología , Pirimidinas/farmacología , Animales , Línea Celular , Relación Dosis-Respuesta a Droga , Electrochoque , Humanos , Canal de Potasio KCNQ2/agonistas , Microsomas/efectos de los fármacos , Estructura Molecular , Piperidinas/administración & dosificación , Piperidinas/química , Pirimidinas/administración & dosificación , Pirimidinas/química , Ratas , Relación Estructura-ActividadRESUMEN
The asymmetric synthesis of (2R,3R)-3-methyl-3-hydroxypipecolic acid, a key intermediate in the synthesis of dual MMP-13/aggrecanase inhibitors, is described. The title compound is prepared in seven steps with an overall yield of 41% starting from geraniol. Key steps in the synthesis include Sharpless asymmetric epoxidation, which establishes the chiral centers, and a one-pot oxidative olefin cleavage/reductive amination sequence that closes the piperidine ring.
Asunto(s)
Ácidos Pipecólicos/síntesis química , Terpenos/química , Monoterpenos Acíclicos , Hidrólisis , Estructura Molecular , Ozono/química , Ácidos Pipecólicos/química , EstereoisomerismoRESUMEN
The design, synthesis, and biological evaluation of potent inhibitors of the TrkA kinase is presented. A homology model is created to aid in the enhancement of potency and selectivity of isothiazole inhibitors found during a high-throughput screen. Three different syntheses are utilized to make diverse analogs within this series. Aminoheterocycles are found to be good urea surrogates, whereas bicyclic substituents on the C3 thio group were found to be extremely potent TrkA inhibitors in kinase and cell assays.
Asunto(s)
Simulación por Computador , Inhibidores Enzimáticos , Receptor trkA/antagonistas & inhibidores , Tiazoles , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Modelos Moleculares , Estructura Molecular , Estereoisomerismo , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/química , Tiazoles/farmacologíaRESUMEN
A series of pipecolic hydroxamate inhibitors of MMP-13 and aggrecanase was discovered based on screening known inhibitors of TNF-alpha converting enzyme (TACE). Potency versus aggrecanase was optimized by modification of the benzyloxyarylsulfonamide group. Incorporation of geminal alkyl substitution at the 3-position of the piperidine ring improved metabolic stability, presumably by increasing steric hindrance around the metabolically labile hydroxamic acid. This modification also resulted in dramatic improvement of aggrecanase activity with a slight reduction in selectivity versus MMP-1. Synthesis, structure activity relationships, and strategies to reduce metabolic clearance are described.
Asunto(s)
Endopeptidasas/efectos de los fármacos , Ácidos Hidroxámicos/farmacología , Inhibidores de la Metaloproteinasa de la Matriz , Inhibidores de Proteasas/farmacología , Ácidos Hidroxámicos/química , Metaloproteinasa 13 de la Matriz , Inhibidores de Proteasas/químicaRESUMEN
A series of 3-hydroxy-3-methylpipecolic hydroxamate inhibitors of MMP-13 and aggrecanase was designed based on the observation of increased aggrecanase activity with substitution at the 3-position of the piperidine ring. Potency versus aggrecanase was optimized by modification of the benzyloxyarylsulfonamide group that binds in the S1' pocket. These compounds also possess markedly improved bioavailability and lower metabolic clearance compared to analogous 3,3-dimethyl-5-hydroxypipecolic hydroxamates. These improvements are attributed to lowered lipophilicity proximal to the metabolically labile hydroxamic acid. Synthesis, structure activity relationships, and in vivo efficacy data are described.
Asunto(s)
Endopeptidasas/efectos de los fármacos , Ácidos Hidroxámicos/síntesis química , Ácidos Hidroxámicos/farmacocinética , Inhibidores de la Metaloproteinasa de la Matriz , Ácidos Pipecólicos/síntesis química , Ácidos Pipecólicos/farmacocinética , Administración Oral , Animales , Colagenasas/metabolismo , Diseño de Fármacos , Endopeptidasas/metabolismo , Humanos , Ácidos Hidroxámicos/química , Metaloproteinasa 13 de la Matriz , Estructura Molecular , Ácidos Pipecólicos/química , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacocinética , Relación Estructura-ActividadRESUMEN
N-Hydroxy-3-hydroxy-4-arylsulfonyltetrahydropyranyl-3-carboxamides were designed as novel inhibitors of MMP-13 and aggrecanase based on known endocyclic hydroxamate inhibitors of matrix metalloproteinases. These compounds offer favorable physicochemical properties and low metabolic clearance. Synthesis and structure-activity relationships are reported.
Asunto(s)
Endopeptidasas/metabolismo , Ácidos Hidroxámicos/síntesis química , Inhibidores de la Metaloproteinasa de la Matriz , Inhibidores de Proteasas/síntesis química , Piranos/síntesis química , Animales , Colagenasas/química , Endopeptidasas/química , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacocinética , Metaloproteinasa 1 de la Matriz/química , Metaloproteinasa 13 de la Matriz , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacocinética , Piranos/química , Piranos/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
A series of novel MMP-13 and TNF-alpha converting enzyme inhibitors based on piperazine 2-hydroxamic acid scaffolds are described. The TACE, MMP-1 and MMP-13 activity of these inhibitors as well as the effect of substitution of the piperazine nitrogen and the P-1' benzyloxy tailpiece is discussed. Moderate in vivo activity is observed with several members of this group.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores de la Metaloproteinasa de la Matriz , Metaloendopeptidasas/antagonistas & inhibidores , Piperazinas/síntesis química , Factor de Necrosis Tumoral alfa/metabolismo , Proteínas ADAM , Proteína ADAM17 , Animales , Colagenasas/metabolismo , Inhibidores Enzimáticos/farmacología , Metaloproteinasa 13 de la Matriz , Metaloendopeptidasas/metabolismo , Piperazinas/farmacología , RatasRESUMEN
A series of novel, selective TNF-alpha converting enzyme inhibitors based on 4-hydroxy and 5-hydroxy pipecolate hydroxamic acid scaffolds is described. The potency and selectivity of TACE inhibition is dramatically influenced by the nature of the sulfonamide group which interacts with the S1' site of the enzyme. Substituted 4-benzyloxybenzenesulfonamides exhibit excellent TACE potency with >100x selectivity over inhibition of matrix metalloprotease-1 (MMP-1). Alkyl substituents on the ortho position of the benzyl ether moiety give the most potent inhibition of TNF-alpha release in LPS-treated human whole blood.