Abstract

A novel series of 3-amino-piperidin-2-one-based calcitonin gene-related peptide (CGRP) receptor antagonists was invented based upon the discovery of unexpected structure–activity observations. Initial exploration of the structure–activity relationships enabled the generation of a moderately potent lead structure (4). A series of modifications, including ring contraction and inversion of stereocenters, led to surprising improvements in CGRP receptor affinity. These studies identified compound 23, a structurally novel potent, orally bioavailable CGRP receptor antagonist.