Identification of a novel benzimidazole derivative as a highly potent NPY Y5 receptor antagonist with an anti-obesity profile.
Optimization of HTS hit 1 for NPY Y5 receptor binding affinity, CYP450 inhibition, solubility and metabolic stability led to the identification of some orally available oxygen-linker derivatives for in vivo study. Among them, derivative 4i inhibited food intake induced by the NPY Y5 selective agonist, and chronic oral administration of 4i in DIO mice caused a dose-dependent reduction of body weight gain.
T1 T2 T3 T4 T5 T6
CHEMICAL CHEMICAL GENE-Y GENE-Y GENE-N GENE-Y
oxygen benzimidazole NPY Y5 NPY Y5 receptor CYP450 NPY Y5 receptor