Discovery of Tetrasubstituted Imidazolines as Potent and Selective Neuropeptide Y Y5 Receptor Antagonists: Reduced Human Ether-a-go-go Related Gene Potassium Channel Binding Affinity and Potent Antiobesity Effect

A series of novel imidazoline derivatives was synthesized and evaluated as neuropeptide Y (NPY) Y5 receptor antagonists. Optimization of previously reported imidazoline leads, <b>1a</b> and <b>1b</b>, was attempted by introduction of substituents at the 5-position on the imidazoline ring and modification of the bis(4-fluorphenyl) moiety. A number of potent derivatives without human ether-a-go-go related gene potassium channel (hERG) activity were identified. Selected compounds, including <b>2a</b>, were shown to have excellent brain and CSF permeability. Compound <b>2a</b> displayed a suitable pharmacokinetic profile for chronic in vivo studies and potently inhibited d-Trp³⁴NPY-induced acute food intake in rats. Oral administration of <b>2a</b> resulted in a potent reduction of body weight in a diet-induced obese mouse model