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

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 terti...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2011-05, Vol.21 (9), p.2683-2686
Hauptverfasser:	Paone, Daniel V., Nguyen, Diem N., Shaw, Anthony W., Burgey, Christopher S., Potteiger, Craig M., Deng, James Z., Mosser, Scott D., Salvatore, Christopher A., Yu, Sean, Roller, Shane, Kane, Stefanie A., Selnick, Harold G., Vacca, Joseph P., Williams, Theresa M.
Format:	Artikel
Sprache:	eng
Schlagworte:	Analgesics, Non-Narcotic - chemical synthesis Analgesics, Non-Narcotic - chemistry Analgesics, Non-Narcotic - pharmacology Animals Azepines - chemical synthesis Azepines - chemistry Azepines - pharmacology Biological and medical sciences Biological Availability Calcitonin gene-related peptide Caprolactam - chemistry Cells, Cultured CGRP Dogs Humans Imidazoles - chemical synthesis Imidazoles - chemistry Imidazoles - pharmacology Inhibitory Concentration 50 Macaca mulatta Medical sciences Migraine Migraine Disorders - drug therapy MK-2918 Molecular Structure Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems Pharmacology. Drug treatments Rats Receptors, Calcitonin Gene-Related Peptide - antagonists & inhibitors Structure-Activity Relationship Telcagepant
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Zusammenfassung:	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).
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2010.12.054