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

• Published in: Bioorganic & medicinal chemistry letters Vol. 22; no. 14; pp. 4719 - 4722
• Main Authors: Chaturvedula, Prasad V., Pin, Sokhom, Tholady, George, Conway, Charlie M., Macor, John E., Dubowchik, Gene M.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.07.2012; Elsevier
• Subjects: antagonists; arteries; Biological and medical sciences; calcitonin; CGRP receptor antagonists; Drug Design; humans; Hydrogen Bonding; Medical sciences; Molecular Structure; oxidative stability; Pharmacology. Drug treatments; Receptors, Calcitonin Gene-Related Peptide - antagonists & inhibitors; Spiro Compounds - chemistry; Spiro Compounds - pharmacology; Structure-Activity Relationship; structure-activity relationships; CGRP receptor antagonists; Antagonist; CGRP receptor; Chemical synthesis; Spiran
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.05.118

We report the synthesis of rigid spirocyclic systems as conformationally constrained variants of the Ala-Phe-NH2 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.