Structure-Based Drug Discovery of HTL22562: a CGRP Receptor Antagonist For Acute Treatment of Migraine
By Sarah Bucknell et al. | Jun 23, 2020
Sarah Bucknell, Senior Scientist II Chemistry, together with fellow scientists from Sosei Heptares and Teva Pharmaceuticals, recently published a paper in the Journal of Medicinal Chemistry, titled "Structure-Based Drug Discovery of N-((R)-3-(7-Methyl-1H-indazol-5-yl)-1-oxo-1-(((S)-1-oxo-3-(piperidin-4-yl)-1-(4-(pyridin-4-yl)piperazin-1-yl)propan-2-yl)amino)propan-2-yl)-2'-oxo-1',2'-dihydrospiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazine]-1-carboxamide (HTL22562): a Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonist For Acute Treatment of Migraine".
Structure-based drug design enabled the discovery of HTL22562, a CGRP receptor antagonist. The structure of HTL22562 complexed with the CGRP receptor was determined at 1.6 Å resolution. Compound HTL22562 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 HTL22562 being taken forward as a clinical candidate for acute treatment of migraine.