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 Receptor Antagonist for Acute Treatment of Migraine

Autor:	Bucknell, Sarah J., Ator, Mark A., Brown, Alastair J. H., Brown, Jason, Cansfield, Andrew D., Cansfield, Julie E., Christopher, John A., Congreve, Miles, Cseke, Gabriella, Deflorian, Francesca, Jones, Christopher R., Mason, Jonathan S., O’Brien, M. Alistair, Ott, Gregory R., Pickworth, Mark, Southall, Stacey M.
Zdroj:	Journal of Medicinal Chemistry; July 2020, Vol. 63 Issue: 14 p7906-7920, 15p
Abstrakt:	Structure-based drug design enabled the discovery of 8, HTL22562, a calcitonin gene-related peptide (CGRP) receptor antagonist. The structure of 8complexed with the CGRP receptor was determined at a 1.6 Å resolution. Compound 8is 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 8being selected as a clinical candidate for acute treatment of migraine.
Databáze:	Supplemental Index
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