RESUMEN
The eukaryotic initiation factor 4E (eIF4E) plays a central role in the initiation of gene translation and subsequent protein synthesis by binding the 5' terminal mRNA cap structure. We designed and synthesized a series of novel compounds that display potent binding affinity against eIF4E despite their lack of a ribose moiety, phosphate, and positive charge as present in m7-GMP. The biochemical activity of compound 33 is 95 nM for eIF4E in an SPA binding assay. More importantly, the compound has an IC(50) of 2.5 µM for inhibiting cap-dependent mRNA translation in a rabbit reticular cell extract assay (RRL-IVT). This series of potent, truncated analogues could serve as a promising new starting point toward the design of neutral eIF4E inhibitors with physicochemical properties suitable for cellular activity assessment.
Asunto(s)
Factor 4E Eucariótico de Iniciación/metabolismo , Guanina/análogos & derivados , Guanosina Monofosfato/análogos & derivados , Guanosina Monofosfato/farmacología , Organofosfonatos/síntesis química , Caperuzas de ARN/metabolismo , Animales , Cristalografía por Rayos X , Diseño de Fármacos , Factor 4E Eucariótico de Iniciación/química , Guanina/síntesis química , Guanina/farmacología , Guanosina Monofosfato/síntesis química , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Organofosfonatos/farmacología , Ácidos Fosforosos , Biosíntesis de Proteínas/efectos de los fármacos , Caperuzas de ARN/química , Conejos , Reticulocitos/efectos de los fármacos , Reticulocitos/metabolismo , Relación Estructura-ActividadRESUMEN
A series of benzodiazepine antagonists of the human ghrelin receptor GHSR1a were synthesized and their antagonism and metabolic stability were evaluated. The potency of these analogs was determined using a functional aequorin (Euroscreen) luminescent assay measuring the intracellular Ca(2+) concentration, and their metabolic stability was measured using an in vitro rat and human S9 hepatocyte assay. These efforts led to the discovery of a potent ghrelin antagonist with good rat pharmacokinetic properties.
Asunto(s)
Benzodiazepinas/química , Benzodiazepinas/farmacología , Receptores de Ghrelina/antagonistas & inhibidores , Receptores de Ghrelina/metabolismo , Animales , Benzodiazepinas/metabolismo , Benzodiazepinas/farmacocinética , Calcio/metabolismo , Línea Celular , Hepatocitos/metabolismo , Humanos , Mediciones Luminiscentes , Obesidad/tratamiento farmacológico , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
The optimization of a series of 8-aza-quinazolinone analogs for antagonist activity against the CXCR3 receptor is reported. Compounds were optimized to avoid the formation of active metabolites and time-dependent-inhibitors of CYP3A4. In addition, antagonists showed potent against CXCR3 activity in whole blood and optimized to avoid activity in the chromosomal aberration assay. Compound 25 was identified as having the optimal balance of CXCR3 activity and pharmacokinetic properties across multiple pre-clinical species, which are reported herein.