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

Autor:	Anthony W. Shaw, Theresa M. Williams, Joseph P. Vacca, Scott D. Mosser, Sean Yu, Christopher A. Salvatore, Craig M. Potteiger, Stefanie A. Kane, Diem N. Nguyen, Christopher S. Burgey, James Z. Deng, Shane Roller, Daniel V. Paone, Harold G. Selnick
Rok vydání:	2011
Předmět:	Migraine Disorders Clinical Biochemistry hERG Biological Availability Pharmaceutical Science Calcitonin gene-related peptide Pharmacology Biochemistry Inhibitory Concentration 50 Structure-Activity Relationship Dogs Calcitonin Gene-Related Peptide Receptor Antagonists Oral administration Drug Discovery Animals Caprolactam Humans Potency Structure–activity relationship Molecular Biology Cells Cultured Telcagepant Molecular Structure biology Chemistry Organic Chemistry Imidazoles Antagonist Azepines Analgesics Non-Narcotic Macaca mulatta In vitro Rats biology.protein Molecular Medicine
Zdroj:	Bioorganic & Medicinal Chemistry Letters. 21:2683-2686
ISSN:	0960-894X
Popis:	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).
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9e6e3b8d2d0a8e489087ed560280589f https://doi.org/10.1016/j.bmcl.2010.12.054 Zobrazit plný text záznamu Full Text from ScienceDirect