Pyrrolidinones as potent functional antagonists of the human melanocortin-4 receptor

A series of pyrrolidinones derived from phenylalaninepiperazines were synthesized and characterized as potent and selective antagonists of the melanocortin-4 receptor. In addition to their high binding affinities, these compounds displayed high functional potencies. 12a had a Ki of 0.94 nM in binding and IC50 of 21 nM in functional activity. 12a also demonstrated efficacy in a mouse cachexia model.