[show abstract][hide abstract] ABSTRACT: A novel series of trans-8-aminomethyl-1-oxa-3-azaspiro[4.5]decan-2-one derivatives was identified with potent NPY Y5 antagonist activity. Optimization of the original lead furnished compounds 23p and 23u, which combine sub-nanomolar Y5 activity with metabolic stability, oral bioavailability, brain penetration and strong preclinical profile for development. Both compounds significantly inhibited the food intake induced by a Y5 selective agonist with minimal effective doses of 3mg/kg po.
[show abstract][hide abstract] ABSTRACT: 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 30mg/kg po.
[show abstract][hide abstract] ABSTRACT: A novel class of small molecule NPY Y5 antagonists based around an azabicyclo[3.1.0]hexane scaffold was identified through modification of a screening hit. Structure-activity relationships and efforts undertaken to achieve a favourable pharmacokinetic profile in rat are described.