RESUMEN
In this Letter we describe the discovery of potent, selective, and orally active aminopurine JNK inhibitors. Improving the physico-chemical properties as well as increasing the potency and selectivity of a subseries with rat plasma exposure, led to the identification of four structurally diverse inhibitors. Differentiation based on PK profiles in multiple species as well as activity in a chronic efficacy model led to the identification of 1 (CC-930) as a development candidate, which is currently in Phase II clinical trial for IPF.
Asunto(s)
Ciclohexanoles/química , Ciclohexanoles/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , MAP Quinasa Quinasa 4/antagonistas & inhibidores , Purinas/química , Purinas/farmacología , Administración Oral , Animales , Dominio Catalítico , Ciclohexanoles/administración & dosificación , Perros , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/administración & dosificación , Haplorrinos , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Concentración 50 Inhibidora , Modelos Moleculares , Estructura Molecular , Purinas/administración & dosificación , Ratas , Relación Estructura-ActividadRESUMEN
In this Letter we describe the optimization of an aminopurine lead (1) with modest potency and poor overall kinase selectivity which led to the identification of a series of potent, selective JNK inhibitors. Improvement in kinase selectivity was enabled by introduction of an aliphatic side chain at the C-2 position. CC-359 (2) was selected as a potential clinical candidate for diseases manifested by ischemia reperfusion injury.
Asunto(s)
2-Aminopurina/química , 2-Aminopurina/farmacología , Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Purinas/química , Daño por Reperfusión/enzimología , Animales , Dominio Catalítico , Perros , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Haplorrinos , Concentración 50 Inhibidora , Modelos Moleculares , Estructura Molecular , Purinas/farmacología , Ratas , Daño por Reperfusión/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
Cardiovascular disease remains the leading cause of mortality in westernized countries, despite optimum medical therapy to reduce the levels of low-density lipoprotein (LDL)-associated cholesterol. The pursuit of novel therapies to target the residual risk has focused on raising the levels of high-density lipoprotein (HDL)-associated cholesterol in order to exploit its atheroprotective effects. MicroRNAs (miRNAs) have emerged as important post-transcriptional regulators of lipid metabolism and are thus a new class of target for therapeutic intervention. MicroRNA-33a and microRNA-33b (miR-33a/b) are intronic miRNAs whose encoding regions are embedded in the sterol-response-element-binding protein genes SREBF2 and SREBF1 (refs 3-5), respectively. These miRNAs repress expression of the cholesterol transporter ABCA1, which is a key regulator of HDL biogenesis. Recent studies in mice suggest that antagonizing miR-33a may be an effective strategy for raising plasma HDL levels and providing protection against atherosclerosis; however, extrapolating these findings to humans is complicated by the fact that mice lack miR-33b, which is present only in the SREBF1 gene of medium and large mammals. Here we show in African green monkeys that systemic delivery of an anti-miRNA oligonucleotide that targets both miR-33a and miR-33b increased hepatic expression of ABCA1 and induced a sustained increase in plasma HDL levels over 12 weeks. Notably, miR-33 antagonism in this non-human primate model also increased the expression of miR-33 target genes involved in fatty acid oxidation (CROT, CPT1A, HADHB and PRKAA1) and reduced the expression of genes involved in fatty acid synthesis (SREBF1, FASN, ACLY and ACACA), resulting in a marked suppression of the plasma levels of very-low-density lipoprotein (VLDL)-associated triglycerides, a finding that has not previously been observed in mice. These data establish, in a model that is highly relevant to humans, that pharmacological inhibition of miR-33a and miR-33b is a promising therapeutic strategy to raise plasma HDL and lower VLDL triglyceride levels for the treatment of dyslipidaemias that increase cardiovascular disease risk.
Asunto(s)
Chlorocebus aethiops , Regulación de la Expresión Génica/efectos de los fármacos , Lipoproteínas HDL/sangre , Lipoproteínas VLDL/sangre , Hígado/efectos de los fármacos , MicroARNs/antagonistas & inhibidores , Oligorribonucleótidos Antisentido/farmacología , Triglicéridos/sangre , Transportador 1 de Casete de Unión a ATP , Transportadoras de Casetes de Unión a ATP/metabolismo , Animales , Células Cultivadas , Chlorocebus aethiops/sangre , Chlorocebus aethiops/genética , Chlorocebus aethiops/metabolismo , LDL-Colesterol/sangre , Silenciador del Gen , Células HEK293 , Humanos , Hígado/metabolismo , Masculino , MicroARNs/metabolismo , Factores de TiempoRESUMEN
Our policy of conducting biotransformation studies with extended chromatography prior to pharmacokinetic bioanalyses allowed us to quickly detect an unusual, cis/trans metabolite in rat plasma that was inseparable using a short chromatographic method. We caution investigators that short methods invite unknown isobaric metabolites to cause inaccuracies in plasma concentration measurements.