RESUMEN
The incorporation of a carboxylic acid within in a series of 3-amido-4-aryl substituted piperidines (represented by general structure 32) led to the discovery of potent, zwitterionic, renin inhibitors with improved off-target profiles (CYP3A4 time-dependent inhibition and hERG affinity) relative to analogous non-zwitterionic inhibitors of the past (i.e., 3). Strategies to address the oral absorption of these zwitterions are also discussed within.
Asunto(s)
Inhibidores de Proteasas/síntesis química , Renina/antagonistas & inhibidores , Administración Oral , Animales , Dominio Catalítico , Simulación por Computador , Perros , Evaluación Preclínica de Medicamentos , Humanos , Piperidinas/síntesis química , Piperidinas/química , Piperidinas/farmacocinética , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacocinética , Ratas , Ratas Sprague-Dawley , Renina/metabolismo , Relación Estructura-ActividadRESUMEN
The discovery of novel and selective inhibitors of human 5-lipoxygenase (5-LO) is described. These compounds are potent, orally bioavailable, and active at inhibiting leukotriene biosynthesis in vivo in a dog PK/PD model. A major focus of the optimization process was to reduce affinity for the human ether-a-go-go gene potassium channel while preserving inhibitory potency on 5-LO. These efforts led to the identification of inhibitor (S)-16 (MK-0633, setileuton), a compound selected for clinical development for the treatment of respiratory diseases.
RESUMEN
Caspase-3 is a cysteinyl protease that mediates apoptotic cell death. Its inhibition may have an important impact on the treatment of several degenerative diseases. Here we report the synthesis of reversible inhibitors via a solid-support palladium-catalyzed amination of 3-bromopyrazinones and the discovery of a pan-caspase reversible inhibitor.
Asunto(s)
Inhibidores de Caspasas , Paladio/química , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Pirazinas/síntesis química , Pirazinas/farmacología , Aminación , Catálisis , Línea Celular , Cromatografía Líquida de Alta Presión , Humanos , Indicadores y Reactivos , Espectrometría de Masas , Proteínas Recombinantes/química , Relación Estructura-ActividadRESUMEN
Leukotriene biosynthesis inhibitors have potential as therapeutic agents for asthma and inflammatory diseases. A novel series of substituted coumarin derivatives has been synthesized and the structure-activity relationship was evaluated with respect to their ability to inhibit the formation of leukotrienes via the human 5-lipoxygenase enzyme.
Asunto(s)
Cumarinas/farmacología , Inhibidores Enzimáticos/farmacología , Inhibidores de la Lipooxigenasa , Cumarinas/síntesis química , Cumarinas/química , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A series of potent and selective inhibitors of the inducible microsomal PGE2 synthase (mPGES-1) has been developed based on the indole FLAP inhibitor MK-886. Compounds 23 and 30 inhibit mPGES-1 with potencies in the low nanomolar range and with selectivities of at least 100-fold compared to their inhibition of mPGES-2, thromboxane synthase and binding affinity to FLAP. They also block the production of PGE2 in cell based assays but with a decreased potency and more limited selectivity compared to the enzyme assays.
Asunto(s)
Inhibidores de la Ciclooxigenasa/síntesis química , Inhibidores de la Ciclooxigenasa/farmacología , Indoles/síntesis química , Indoles/farmacología , Oxidorreductasas Intramoleculares/antagonistas & inhibidores , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Inhibidores de la Ciclooxigenasa/química , Humanos , Indoles/química , Microsomas/enzimología , Prostaglandina-E Sintasas , Relación Estructura-ActividadRESUMEN
Caspase 3 is a cysteinyl protease that mediates apoptotic cell death. Its inhibition may have an important impact in the treatment of several degenerative diseases. The P1 aspartic acid residue is a required element of recognition for this enzyme that was maintained constant along with the adjacent natural valine as the P2 group. The thiobenzylmethylketone warhead on the aspartate was conveniently handled through solid-phase synthesis allowing modification in the P3 region that eventually led to simpler derivatives with increased potency against caspase 3. The key to such an effect is the introduction of hydroxyl group alpha to the P3 carbonyl.
Asunto(s)
Inhibidores de Caspasas , Dipéptidos/síntesis química , Cetonas/síntesis química , Ácido Aspártico , Caspasa 3 , Técnicas Químicas Combinatorias , Dipéptidos/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Humanos , Enlace de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Concentración 50 Inhibidora , Cetonas/farmacología , Proteínas Recombinantes , Relación Estructura-Actividad , ValinaRESUMEN
The introduction of a hydroxyl group into the 5-position of the diaryl furanone system provides highly selective inhibitors of cyclooxygenase-2. These molecules can be converted into their sodium salts which are water soluble, facilitating intravenous formulation. These salts show excellent potency in rat models of pain, fever and inflammation.
Asunto(s)
Inhibidores de la Ciclooxigenasa/síntesis química , Inhibidores de la Ciclooxigenasa/farmacología , Furanos/síntesis química , Furanos/farmacología , Isoenzimas/metabolismo , Prostaglandina-Endoperóxido Sintasas/metabolismo , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/farmacología , Artritis Experimental/tratamiento farmacológico , Células CHO , Fenómenos Químicos , Química Física , Cricetinae , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Edema/inducido químicamente , Edema/prevención & control , Fiebre/inducido químicamente , Fiebre/tratamiento farmacológico , Humanos , Proteínas de la Membrana , Dolor/inducido químicamente , Dolor/tratamiento farmacológico , Ratas , Solubilidad , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
A robust method for the solid phase synthesis of a series of selective caspase-3 peptide inhibitors is described. The inhibitors can be obtained after cleavage from the solid support without further purification.
Asunto(s)
Inhibidores de Caspasas , Oligopéptidos/síntesis química , Oligopéptidos/farmacología , Caspasa 3 , Línea Celular , Supervivencia Celular/efectos de los fármacos , Técnicas Químicas Combinatorias , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 InhibidoraRESUMEN
The discovery of a series of potent, selective and reversible dipeptidyl caspase-3 inhibitors are reported. The iterative discovery process of using combinatorial chemistry, parallel synthesis, moleculare modelling and structural biology will be discussed.
Asunto(s)
Ácido Aspártico/química , Inhibidores de Caspasas , Dipéptidos , Inhibidores Enzimáticos , Cetonas , Sitios de Unión , Caspasa 3 , Células Cultivadas , Técnicas Químicas Combinatorias , Dipéptidos/síntesis química , Dipéptidos/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Humanos , Cetonas/síntesis química , Cetonas/farmacología , Modelos Moleculares , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
Caspase-3 is a cysteinyl protease that mediates apoptotic cell death. Its inhibition may have an important impact in the treatment of several degenerative diseases. Since P(1) aspartic acid is a required element of recognition for this enzyme, a library of capped aspartyl aldehydes was synthesized using solid-phase chemistry. The 5-bromonicotinamide derivative of the aspartic acid aldehyde was identified to be an inhibitor of caspase-3. Substitution at the 5-position of the pyridine ring and conversion of the aldehyde to ketones led to a series of potent inhibitors of caspase-3.