Design, synthesis and SAR of a novel series of benzimidazoles as potent NPY Y5 antagonists

The synthesis and SAR of a series of potent NPY Y5 antagonists is reported. Optimisation led to the identification of compounds 9b (fp K i = 9.2). A novel class of benzimidazole NPY Y5 receptor antagonists was prepared exploiting a privileged spirocarbamate moiety. The structure–activity relationship of this series and efforts to achieve a profile suitable for further development and an appropriate pharmacokinetic profile in rat are described. Optimisation led to the identification of the brain penetrant, orally bioavailable Y5 antagonist 9b which significantly inhibited the food intake induced by a Y5 selective agonist with a minimal effective dose of 30 mg/kg po.