RESUMEN
Metachromatic leukodystrophy (MLD) is a rare, genetic lysosomal storage disorder caused by the deficiency of arylsulfatase A enzyme, which results in the accumulation of sulfatide in the lysosomes of the tissues of central and peripheral nervous systems, leading to progressive demyelination and neurodegeneration. Currently there is no cure for this disease, and the only approved therapy, hematopoietic stem cell transplant, has limitations. We proposed substrate reduction therapy (SRT) as a novel approach to treat this disease, by inhibiting ceramide galactosyltransferase enzyme (UGT8). This resulted in the identification of a thienopyridine scaffold as a starting point to initiate medicinal chemistry. Further optimization of hit compound 1 resulted in the identification of brain penetrable, orally bioavailable compound 19, which showed efficacy in the in vivo pharmacodynamic models, indicating the potential to treat MLD with UGT8 inhibitors.
RESUMEN
N-substituted azaindoles were discovered as potent pan-PIM inhibitors. Lead optimization, guided by structure and focused on physico-chemical properties allowed us to solve inherent hERG and permeability liabilities, and provided compound 27, which subsequently impacted KG-1 tumor growth in a mouse model.
Asunto(s)
Antineoplásicos/farmacología , Compuestos Aza/farmacología , Indoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Compuestos Aza/síntesis química , Compuestos Aza/metabolismo , Línea Celular Tumoral , Cristalografía por Rayos X , Humanos , Indoles/síntesis química , Indoles/metabolismo , Ratones , Piperidinas/síntesis química , Piperidinas/metabolismo , Piperidinas/farmacología , Unión Proteica , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-pim-1/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-pim-1/metabolismo , Pirrolidinas/síntesis química , Pirrolidinas/metabolismo , Pirrolidinas/farmacología , Ratas , Estereoisomerismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
N-substituted azaindoles were discovered as promising pan-PIM inhibitors. Lead optimization is described en route toward the identification of a clinical candidate. Modulation of physico-chemical properties allowed to solve inherent hERG and permeability liabilities. Compound 17 showed tumor growth inhibition in a KG1 tumor-bearing mouse model.
Asunto(s)
Antineoplásicos/farmacología , Descubrimiento de Drogas , Indoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-pim-1/antagonistas & inhibidores , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Indoles/administración & dosificación , Indoles/química , Ratones , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-pim-1/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
N-Substituted azaindoles have been discovered as pan-PIM kinase inhibitors. Initial SAR, early ADME and PK/PD data of a series of compounds is described and led to the identification of promising pan-PIM inhibitors which validated our interest in the 7-azaindole scaffold and led us to pursue the identification of a clinical candidate.
Asunto(s)
Indoles/química , Indoles/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-pim-1/metabolismo , Animales , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Activación Enzimática/efectos de los fármacos , Semivida , Humanos , Indoles/metabolismo , Concentración 50 Inhibidora , Ratones , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Proto-Oncogénicas c-pim-1/química , Ratas , Relación Estructura-ActividadRESUMEN
A solid phase combinatorial library was designed based on X-ray structures and in-silico models to explore an inducible S4+ pocket, which is formed by a simple side-chain rotation of Tyr95. This inducible S4+ pocket is unique to ß-tryptase and does not exist for other trypsin-like serine proteases of interest. Therefore, inhibitors utilizing this pocket have inherent advantages for being selective against other proteases in the same family. A member of this library was found to be a potent and selective ß-tryptase inhibitor with a suitable pharmacokinetic profile for further clinical evaluation.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Mastocitos/enzimología , Bibliotecas de Moléculas Pequeñas/farmacología , Triptasas/antagonistas & inhibidores , Administración Oral , Animales , Técnicas Químicas Combinatorias , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/síntesis química , Humanos , Modelos Moleculares , Estructura Molecular , Ratas , Proteínas Recombinantes/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/administración & dosificación , Bibliotecas de Moléculas Pequeñas/síntesis química , Relación Estructura-ActividadRESUMEN
A new series of novel mast cell tryptase inhibitors is reported, which features the use of an indole structure as the hydrophobic substituent on a m-benzylaminepiperidine template. The best members of this series display good in vitro activity and excellent selectivity against other serine proteases.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Mastocitos/enzimología , Serina Endopeptidasas/efectos de los fármacos , Inhibidores Enzimáticos/química , Modelos Moleculares , Relación Estructura-Actividad , TriptasasRESUMEN
Tryptase is a serine protease found almost exclusively in mast cells. It has trypsin-like specificity, favoring cleavage of substrates with an arginine (or lysine) at the P1 position, and has optimal catalytic activity at neutral pH. Current evidence suggests tryptase beta is the most important form released during mast cell activation in allergic diseases. It is shown to have numerous pro-inflammatory cellular activities in vitro, and in animal models tryptase provokes broncho-constriction and induces a cellular inflammatory infiltrate characteristic of human asthma. Screening of in-house inhibitors of factor Xa (a closely related serine protease) identified beta-amidoester benzamidines as potent inhibitors of recombinant human betaII tryptase. X-ray structure driven template modification and exchange of the benzamidine to optimize potency and pharmacokinetic properties gave selective, potent and orally bioavailable 4-(3-aminomethyl phenyl)piperidinyl-1-amides.
Asunto(s)
Amidas , Piperidinas , Serina Endopeptidasas/efectos de los fármacos , Administración Oral , Amidas/síntesis química , Amidas/química , Amidas/farmacología , Animales , Disponibilidad Biológica , Células CACO-2 , Cristalografía por Rayos X , Diseño de Fármacos , Inhibidores del Factor Xa , Humanos , Hígado/enzimología , Modelos Moleculares , Estructura Molecular , Piperidinas/síntesis química , Piperidinas/química , Piperidinas/farmacología , Conformación Proteica , Ratas , Proteínas Recombinantes/efectos de los fármacos , Inhibidores de Serina Proteinasa/síntesis química , Inhibidores de Serina Proteinasa/química , Inhibidores de Serina Proteinasa/farmacología , Relación Estructura-Actividad , TriptasasRESUMEN
We exploit the concept of using hydrogen bonds to link multiple ligands for maintaining simultaneous interactions with polyvalent binding sites. This approach is demonstrated by the syntheses and evaluation of pseudo-bivalent ligands as potent inhibitors of human beta-tryptase.