Discovery of potent, cyclic calcitonin gene-related peptide receptor antagonists (pages 383–386)
Liang Zeng Yan, Kirk W. Johnson, Emily Rothstein, David Flora, Patrick Edwards, Baolin Li, Junqing Li, Renee Lynch, Renee Vaughn, Amy Clemens-Smith, Deborah McCarty, Charles Chow, Kevin L. McKnight, Jirong Lu, Eric S Nisenbaum and John P. Mayer
Version of Record online: 15 MAR 2011 | DOI: 10.1002/psc.1358
Calcitonin Gene-Related Peptide (CGRP), a potent dilator of cerebral vasculature is known to be elevated in plasma and cerebrospinal fluid during migraine attacks. Our efforts to develop CGRP antagonists focused on the C-terminal portion of the natural peptide ligand known to bind the receptor but lack agonist properties. Extensive SAR studies identified a novel cyclic structure: (4-fluoro-benzoyl)-(D-Val)-Tyr-cyclo[Cys-Dap-Asp-Val-Gly-Pro-Phe-Cys]-3Pal-NH2 (35) with a Kb value of 0.0491 nM against the cloned hCGRP1 receptor.