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

Prasad V Chaturvedula; Sokhom Pin; George Tholady; Charlie M Conway; John E Macor; Gene M Dubowchik

doi:10.1016/j.bmcl.2012.05.118

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

Bioorg Med Chem Lett. 2012 Jul 15;22(14):4719-22. doi: 10.1016/j.bmcl.2012.05.118. Epub 2012 Jun 9.

Authors

Prasad V Chaturvedula¹, Sokhom Pin, George Tholady, Charlie M Conway, John E Macor, Gene M Dubowchik

Affiliation

¹ Department of Molecular Sciences, Bristol-Myers Squibb R&D, 5 Research Parkway, Wallingford, CT 06492, USA. prasad.chaturvedula@bms.com

PMID: 22732695
DOI: 10.1016/j.bmcl.2012.05.118

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.

MeSH terms

Calcitonin Gene-Related Peptide Receptor Antagonists*
Drug Design
Hydrogen Bonding
Molecular Structure
Spiro Compounds / chemistry*
Spiro Compounds / pharmacology
Structure-Activity Relationship

Substances

Calcitonin Gene-Related Peptide Receptor Antagonists
Spiro Compounds