RESUMEN
We report on the development of a series of pyrimidine carboxylic acids that are potent and selective inhibitors of kynurenine monooxygenase and competitive for kynurenine. We describe the SAR for this novel series and report on their inhibition of KMO activity in biochemical and cellular assays and their selectivity against other kynurenine pathway enzymes. We describe the optimization process that led to the identification of a program lead compound with a suitable ADME/PK profile for therapeutic development. We demonstrate that systemic inhibition of KMO in vivo with this lead compound provides pharmacodynamic evidence for modulation of kynurenine pathway metabolites both in the periphery and in the central nervous system.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Enfermedad de Huntington/tratamiento farmacológico , Quinurenina 3-Monooxigenasa/antagonistas & inhibidores , Pirimidinas/farmacología , Animales , Células CHO , Proliferación Celular/efectos de los fármacos , Cricetulus , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Enfermedad de Huntington/metabolismo , Quinurenina/metabolismo , Quinurenina 3-Monooxigenasa/metabolismo , Ratones , Modelos Moleculares , Estructura Molecular , Pirimidinas/síntesis química , Pirimidinas/química , Ratas , Relación Estructura-ActividadRESUMEN
Tissue transglutaminase 2 (TG2) is a multifunctional protein primarily known for its calcium-dependent enzymatic protein cross-linking activity via isopeptide bond formation between glutamine and lysine residues. TG2 overexpression and activity have been found to be associated with Huntington's disease (HD); specifically, TG2 is up-regulated in the brains of HD patients and in animal models of the disease. Interestingly, genetic deletion of TG2 in two different HD mouse models, R6/1 and R6/2, results in improved phenotypes including a reduction in neuronal death and prolonged survival. Starting with phenylacrylamide screening hit 7d, we describe the SAR of this series leading to potent and selective TG2 inhibitors. The suitability of the compounds as in vitro tools to elucidate the biology of TG2 was demonstrated through mode of inhibition studies, characterization of druglike properties, and inhibition profiles in a cell lysate assay.
Asunto(s)
Acrilamidas/síntesis química , Proteínas de Unión al GTP/antagonistas & inhibidores , Enfermedad de Huntington/tratamiento farmacológico , Sulfonamidas/síntesis química , Transglutaminasas/antagonistas & inhibidores , Acrilamidas/química , Acrilamidas/farmacología , Animales , Células CACO-2 , Permeabilidad de la Membrana Celular , Células HEK293 , Humanos , Técnicas In Vitro , Masculino , Ratones , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Piperazinas/síntesis química , Piperazinas/química , Piperazinas/farmacología , Proteína Glutamina Gamma Glutamiltransferasa 2 , Piridinas/síntesis química , Piridinas/química , Piridinas/farmacología , Pirimidinas/síntesis química , Pirimidinas/química , Pirimidinas/farmacología , Ratas , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacologíaRESUMEN
Heat shock protein 90 (Hsp90) plays a key role in stress response and protection of the cell against the effects of mutation. Herein we report the identification of an Hsp90 inhibitor identified by fragment screening using a high-concentration biochemical assay, as well as its optimisation by in silico searching coupled with a structure-based drug design (SBDD) approach.