RESUMEN
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
Inhibition of intestinal brush border DMT1 offers a novel therapeutic approach to the prevention and treatment of disorders of iron overload. Several series of diaryl and tricyclic benzylisothiourea compounds as novel and potent DMT1 inhibitors were discovered from the original hit compound 1. These compounds demonstrated in vitro potency against DMT1, desirable cell permeability properties and a dose-dependent inhibition of iron uptake in an acute rat model of iron hyperabsorption. Tricyclic compounds increased the in vitro potency by up to 16-fold versus the original hit. Diaryl compounds 6b and 14a demonstrated significant iron absorption inhibition in vivo with both 25 and 50 mg/kg doses. The diaryl and tricyclic compounds described in this report represent promising structural templates for further optimization.