Design and synthesis of potent antagonists containing rigid spirocyclic privileged structures for the CGRP receptor

Abstract We report the synthesis of rigid spirocyclic systems as conformationally constrained variants of the Ala-Phe-NH 2 dipeptide amide C-terminus of the calcitonin gene-related peptide (CGRP). CGRP receptor antagonists containing these moieties displayed potent affinity, functional antagonism and excellent oxidative stability. Structure–activity relationship studies demonstrated the relative importance of hydrogen bond donor/acceptor functionalities and the preferred orientation of an aromatic ring. Antagonists showed potent and full reversal of CGRP-induced dilation of ex vivo human intracranial arteries.