Discovery of potent, cyclic calcitonin gene-related peptide receptor antagonists

Calcitonin gene‐related peptide (CGRP), a potent dilator of cerebral and dural vasculature, is known to be elevated in plasma and cerebral spinal fluid during migraine attacks. Selective blockade of the CGRP receptor offers the promise of controlling migraine headache more effectively and without the side‐effects associated with the use of triptans. Our efforts to develop a novel, peptide‐based CGRP antagonist focused on the C‐terminal portion of the peptide which is known to bind the receptor but lack agonist properties. Extensive SAR studies of the C‐terminal CGRP (27–37) region identified a novel cyclic structure: Bz‐Val‐Tyr‐cyclo[Cys‐Thr‐Asp‐Val‐Gly‐Pro‐Phe‐Cys]‐Phe‐NH2 (23) with a kb value of 0.126 nM against the cloned human CGRP receptor. Additional SAR studies directed at enhancement of potency and improvement of physicochemical properties yielded a series of analogs with kb values in the 0.05–0.10 nM range. Copyright © 2011 European Peptide Society and John Wiley & Sons, Ltd. 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.