Orally bioavailable imidazoazepanes as calcitonin gene-related peptide (CGRP) receptor antagonists: discovery of MK-2918.

Abstract

In our ongoing efforts to develop CGRP receptor antagonists for the treatment of migraine, we aimed to improve upon telecagepant by targeting a compound with a lower projected clinical dose. Imidazoazepanes were identified as potent caprolactam replacements and SAR of the imidazole yielded the tertiary methyl ether as an optimal substituent for potency and hERG selectivity. Combination with the azabenzoxazinone spiropiperidine ultimately led to preclinical candidate 30 (MK-2918).

• Authors: Daniel V Paone, Diem N Nguyen, Anthony W Shaw, Christopher S Burgey, Craig M Potteiger, James Z Deng, Scott D Mosser, Christopher A Salvatore, Sean Yu, Shane Roller, Stefanie A Kane, Harold G Selnick, Joseph P Vacca, Theresa M Williams
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 21 Issue 9 Pg. 2683-6 (May 01 2011) ISSN: 1464-3405 [Electronic] England
• PMID: 21251825 (Publication Type: Journal Article)
• Copyright: Copyright © 2010 Elsevier Ltd. All rights reserved.

Chemical References

• Analgesics, Non-Narcotic
• Azepines
• Calcitonin Gene-Related Peptide Receptor Antagonists
• Imidazoles
• MK 2918
• Caprolactam

Topics

• Analgesics, Non-Narcotic (chemical synthesis, chemistry, pharmacology)
• Animals
• Azepines (chemical synthesis, chemistry, pharmacology)
• Biological Availability
• Calcitonin Gene-Related Peptide Receptor Antagonists
• Caprolactam (chemistry)
• Cells, Cultured
• Dogs
• Humans
• Imidazoles (chemical synthesis, chemistry, pharmacology)
• Inhibitory Concentration 50
• Macaca mulatta
• Migraine Disorders (drug therapy)
• Molecular Structure
• Rats
• Structure-Activity Relationship