RESUMEN
Stearoyl-CoA desaturase-1 (SCD1) plays an important role in lipid metabolism. Inhibition of SCD1 activity represents a potential novel approach for the treatment of metabolic diseases such as obesity, type 2 diabetes and dyslipidemia, as well as skin diseases, acne and cancer. Herein, we report the synthesis and structure-activity relationships (SAR) of a series of novel triazolone derivatives, culminating in the identification of pyrazolyltriazolone 17a, a potent SCD1 inhibitor, which reduced plasma C16:1/C16:0 triglycerides desaturation index (DI) in an acute Lewis rat model in a dose dependent manner, with an ED50 of 4.6 mg/kg. In preliminary safety studies, compound 17a did not demonstrate adverse effects related to SCD1 inhibition after repeat dosing at 100mg/kg. Together, these data suggest that sufficient safety margins can be achieved with certain SCD1 inhibitors, thus allowing exploration of clinical utility in metabolic disease settings.
Asunto(s)
Estearoil-CoA Desaturasa/antagonistas & inhibidores , Triazoles/química , Triazoles/farmacología , Animales , Descubrimiento de Drogas , Células Hep G2 , Humanos , Metabolismo de los Lípidos/efectos de los fármacos , Enfermedades Metabólicas/tratamiento farmacológico , Ratones , Ratas , Ratas Endogámicas Lew , Relación Estructura-ActividadRESUMEN
We discovered a series of novel and potent thiazolylpyridinone-based SCD1 inhibitors based on a 2-aminothiazole HTS hit by replacing the amide bond with a pyridinone moiety. Compound 19 demonstrated good potency against SCD1 in vitro and in vivo. The mouse liver microsomal SCD1 in vitro potency for 19 was improved by more than 240-fold compared to the original HTS hit. Furthermore, 19 demonstrated a dose-dependent reduction of plasma desaturation index with an ED50 of 6.3 mg/kg. Compound 19 demonstrated high liver to plasma and liver to eyelid exposures, indicating preferential liver distribution. The preliminary toxicology study with compound 19 did not demonstrate adverse effects related to SCD1 inhibition, suggesting a wide safety margin with respect to other known SCD1 inhibitors with wider distribution profiles.
Asunto(s)
Descubrimiento de Drogas/métodos , Hígado/metabolismo , Piridonas/metabolismo , Piridonas/farmacología , Estearoil-CoA Desaturasa/antagonistas & inhibidores , Estearoil-CoA Desaturasa/metabolismo , Animales , Células CACO-2 , Relación Dosis-Respuesta a Droga , Células Hep G2 , Humanos , Hígado/efectos de los fármacos , Ratones , Piridonas/química , Ratas , Ratas Endogámicas Lew , Distribución Tisular/efectos de los fármacos , Distribución Tisular/fisiologíaRESUMEN
Several five- and six-membered heterocycles were introduced to replace the C2-position amide bond of the original 2-aminothiazole-based hit compound 5. Specifically, replacement of the amide bond with an imidazolidinone moiety yielded a novel and potent thiazolylimidazolidinone series of SCD1 inhibitors. XEN723 (compound 22) was identified after optimization of the thiazolylimidazolidinone series. This compound demonstrated a 560-fold improvement in in vitro potency and reduced plasma desaturation indices in a dose dependent manner, with an EC50 of 4.5 mg/kg.
Asunto(s)
Amidas/química , Descubrimiento de Drogas/métodos , Imidazolidinas/química , Enfermedades Metabólicas , Estearoil-CoA Desaturasa/antagonistas & inhibidores , Amidas/farmacología , Amidas/uso terapéutico , Animales , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Femenino , Células Hep G2 , Humanos , Imidazolidinas/farmacología , Imidazolidinas/uso terapéutico , Enfermedades Metabólicas/tratamiento farmacológico , Enfermedades Metabólicas/enzimología , Ratones , Ratas , Ratas Sprague-Dawley , Estearoil-CoA Desaturasa/metabolismoRESUMEN
Stearoyl-CoA desaturase-1 (SCD1) catalyzes de novo synthesis of monounsaturated fatty acids from saturated fatty acids. Studies have demonstrated that rodents lacking a functional SCD1 gene have an improved metabolic profile, including reduced weight gain, lower triglycerides, and improved insulin response. In this study, we discovered a series of piperazinylpyridazine-based highly potent, selective, and orally bioavailable compounds. Particularly, compound 49 (XEN103) was highly active in vitro (mSCD1 IC(50) = 14 nM and HepG2 IC(50) = 12 nM) and efficacious in vivo (ED(50) = 0.8 mg/kg). It also demonstrated striking reduction of weight gain in a rodent model. Our findings with small-molecule SCD1 inhibitors confirm the importance of this target in metabolic regulation, describe novel models for assessing SCD1 inhibitors for efficacy and tolerability and demonstrate an opportunity to develop a novel therapy for metabolic disease.
Asunto(s)
Inhibidores Enzimáticos/uso terapéutico , Síndrome Metabólico/tratamiento farmacológico , Obesidad/tratamiento farmacológico , Piperazinas/uso terapéutico , Piridazinas/uso terapéutico , Estearoil-CoA Desaturasa/antagonistas & inhibidores , Animales , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Espectroscopía de Resonancia Magnética , Ratones , Piperazinas/química , Piperazinas/farmacología , Piridazinas/química , Piridazinas/farmacología , Ratas , Ratas Zucker , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
In this study we demonstrate the use of a multiplexed MRM-based assay to distinguish among normal (NL) and iron-metabolism disorder mouse models, particularly, iron-deficiency anemia (IDA), inflammation (INFL), and inflammation and anemia (INFL+IDA). Our initial panel of potential biomarkers was based on the analysis of 14 proteins expressed by candidate genes involved in iron transport and metabolism. Based on this study, we were able to identify a panel of 8 biomarker proteins: apolipoprotein A4 (APO4), transferrin, transferrin receptor 1, ceruloplasmin, haptoglobin, lactoferrin, hemopexin, and matrix metalloproteinase-8 (MMP8) that clearly distinguish among the normal and disease models. Within this set of proteins, transferrin showed the best individual classification accuracy over all samples (72%) and within the NL group (94%). Compared to the best single-protein biomarker, transferrin, the use of the composite 8-protein biomarker panel improved the classification accuracy from 94% to 100% in the NL group, from 50% to 72% in the INFL group, from 66% to 96% in the IDA group, and from 79% to 83% in the INFL+IDA group. Based on these findings, validation of the utility of this potentially important biomarker panel in human samples in an effort to differentiate IDA, inflammation, and combinations thereof, is now warranted. This article is part of a Special Section entitled: Understanding genome regulation and genetic diversity by mass spectrometry.
Asunto(s)
Anemia Ferropénica/sangre , Anemia Ferropénica/diagnóstico , Anemia/sangre , Anemia/diagnóstico , Proteínas Sanguíneas/análisis , Inflamación/complicaciones , Espectrometría de Masas/métodos , Anemia/etiología , Animales , Biomarcadores/sangre , Proteínas Sanguíneas/química , Diagnóstico Diferencial , Femenino , Inflamación/sangre , Inflamación/diagnóstico , Ratones , Ratones Endogámicos C57BL , Mapeo Peptídico/métodos , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
PURPOSE: The purpose of this study was the use of animal models to demonstrate the importance of drug delivery (verteporfin) to plasma lipoproteins in order to attain efficacy of photodynamic therapy (PDT) in vivo. METHODS: Photosensitizers appropriately formulated in various vehicles such as pluronics and lipid-based systems were compared to delivery of the drug in DMSO in two in vivo systems. The first was a tumor model using male DBA/2 mice inoculated intradermally with M1 rhabdomyosarcoma cells and in the second, arthritis in the MRL -lpr mouse strain was enhanced by two intradermal injections of complete Freunds adjunct. RESULTS: Those formulations in which the drug was in a monomeric form were better able to transfer drug to lipoproteins, which in turn led to superior PDT in vivo. CONCLUSIONS: The ability to introduce drug in monomeric form into the circulation correlates well with efficacy of photosensitizer formulations in mouse arthritis and tumor models.