Structure-activity relationships of a series of pyrrolo[3,2-d]pyrimidine derivatives and related compounds as neuropeptide Y5 receptor antagonists

Neuropeptide Y (NPY) has been shown to play an important role in the regula tion of food intake and energy balance. Pharmacological data suggests that the Y5 receptor subtype contributes to the effects of NPY on appetite, and therefore a Y5 antagonist might be a useful therapeutic agent for the treat ment of obesity. In attempts to identify potential Y5 antagonists, a series of pyrrolo[3,2-d]pyrimidine derivatives was prepared and evaluated for the ir ability to bind to Y5 receptors in vitro. We report here the synthesis a nd initial structure-activity relationship investigations for this class of compounds. The target compounds were prepared by a variety of synthetic ro utes designed to modify both the substitution and the heterocyclic core of the pyrrolo[3,2-d]pyrimidine lead 1. In addition to identifying several pot ent Y5 antagonists for evaluation as potential antiobesity agents, a pharma cophore model, for the human Y5 receptor is presented.