BIIE-0246 is a potent and highly selective non-peptide neuropeptide Y (NPY) Y2 receptor antagonist. With an IC50 of 15 nM.

Receptor binding assays in HEK 293 cells transfected with the rat Y2 receptor cDNA demonstrate that BIIE-0246 competes with high affinity (IC50=15±3 nM) against specific [125I]PYY3-36 binding sites. In contrast, BIIE-0246, at concentrations up to 10 μM, fails to compete for significant amounts of specific [125I]GR231118, [125I]hPP and [125I][Leu31, Pro34]PYY binding sites in HEK 293 cells transfected with the rat Y1, Y4 or Y5 receptor cDNA, respectively[1].

BIIE-0246 does not significantly influence fat mass gain overall. In diet-induced obesity (DIO) models, its impact on body weight and composition varies by genotype, showing a significant treatment×genotype interaction in terms of body weight, fat mass, and lean mass. Specifically, in DIO-NPY models, BIIE-0246 effectively reduces fat mass gain. In genetically obese NPY mice fed a regular chow diet, an increase in body weight and adiposity is observed, yet BIIE-0246 administration leads to weight gain across both studied genotypes within 4.5 weeks, noticeable as early as 2 weeks. For the DIO-WT group, further analysis reveals a rise in body weight and fat mass, alongside a possible reduction in lean mass. Intriguingly, WT mice show an elevated cholesterol level after 2 weeks of BIIE-0246 treatment, which is not observed at the 4.5-week mark. In DIO-NPY mice across treatment conditions, there is a positive correlation between cholesterol levels and body fat mass, not seen in other groups. Moreover, treatment with BIIE-0246 in DIO-NPY mice significantly alters the relationship between cholesterol and fat mass compared to the vehicle-treated group.