Papers of the Week

Structure-based drug design enabled the discovery of 8, HTL22562, a CGRP receptor antagonist. The structure of 8 complexed with the CGRP receptor was determined at 1.6 Å resolution. Compound 8 is a highly potent, selective, metabolically stable and soluble compound suitable for a range of administration routes that have the potential to provide rapid systemic exposures with resultant high levels of receptor coverage (e.g. subcutaneous). The low lipophilicity coupled with a low anticipated clinically efficacious plasma exposure for migraine also suggests a reduced potential for hepatotoxicity. These properties have led to 8 being taken forward as a clinical candidate for acute treatment of migraine.