6zis
Crystal structure of a CGRP receptor ectodomain heterodimer with bound high affinity inhibitor
Structural highlights
Publication Abstract from PubMedStructure-based drug design enabled the discovery of 8, HTL22562, a calcitonin gene-related peptide (CGRP) receptor antagonist. The structure of 8 complexed with the CGRP receptor was determined at a 1.6 A 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 selected as a clinical candidate for acute treatment of migraine. 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'-dihydrosp iro[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.,Bucknell SJ, Ator MA, Brown AJH, Brown J, Cansfield AD, Cansfield JE, Christopher JA, Congreve M, Cseke G, Deflorian F, Jones CR, Mason JS, O'Brien MA, Ott GR, Pickworth M, Southall SM J Med Chem. 2020 Jul 8. doi: 10.1021/acs.jmedchem.0c01003. PMID:32558564[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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