RESUMEN
Glycogen synthase kinase-3 (GSK-3) regulates multiple cellular processes in diabetes, oncology, and neurology. N-(3-(1H-1,2,4-triazol-1-yl)propyl)-5-(3-chloro-4-methoxyphenyl)oxazole-4-carboxamide (PF-04802367 or PF-367) has been identified as a highly potent inhibitor, which is among the most selective antagonists of GSK-3 to date. Its efficacy was demonstrated in modulation of tau phosphorylation inâ vitro and inâ vivo. Whereas the kinetics of PF-367 binding in brain tissues are too fast for an effective therapeutic agent, the pharmacokinetic profile of PF-367 is ideal for discovery of radiopharmaceuticals for GSK-3 in the central nervous system. A (11) C-isotopologue of PF-367 was synthesized and preliminary PET imaging studies in non-human primates confirmed that we have overcome the two major obstacles for imaging GSK-3, namely, reasonable brain permeability and displaceable binding.
Asunto(s)
Encéfalo/efectos de los fármacos , Encéfalo/diagnóstico por imagen , Neuroimagen , Oxazoles/farmacología , Tomografía de Emisión de Positrones , Inhibidores de Proteínas Quinasas/farmacología , Triazoles/farmacología , Proteínas tau/antagonistas & inhibidores , Encéfalo/metabolismo , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3/metabolismo , Humanos , Modelos Moleculares , Estructura Molecular , Oxazoles/síntesis química , Oxazoles/química , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Triazoles/síntesis química , Triazoles/química , Proteínas tau/metabolismoRESUMEN
Explorations in the pyrimidinetrione series of MMP-13 inhibitors led to the discovery of a series of spiro-fused compounds that are potent and selective inhibitors of MMP-13. While other spiro-fused motifs are hydrolytically unstable, presumably due to electronic destabilization of the pyrimidinetrione ring, the spiropyrrolidine series does not share this liability. Greater than 100-fold selectivity versus other MMP family members was achieved by incorporation of an extended aryl-heteroaryl P1'group. When dosed as the sodium salt, these compounds displayed excellent oral absorption and pharmacokinetic properties. Despite the selectivity, a representative of this series produced fibroplasia in a 14 day rat study.
Asunto(s)
Inhibidores de la Metaloproteinasa de la Matriz , Inhibidores de Proteasas/química , Pirimidinas/química , Pirrolidinas/química , Compuestos de Espiro/química , Animales , Estabilidad de Enzimas/efectos de los fármacos , Metaloproteinasa 13 de la Matriz/metabolismo , Inhibidores de Proteasas/farmacología , Pirimidinas/farmacología , Pirrolidinas/farmacología , Ratas , Compuestos de Espiro/farmacología , Relación Estructura-ActividadRESUMEN
Using SAR from two related series of pyrimidinetrione-based inhibitors, compounds with potent MMP-13 inhibition and >100-fold selectivity against other MMPs have been identified. Despite high molecular weights, clogPs, and polar surface areas, the compounds are generally well absorbed and have excellent pharmacokinetic (PK) properties when dosed as sodium salts. In a rat fibrosis model, a compound from the series displayed no fibrosis at exposures many fold greater than its MMP-13 IC50.
