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

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 excellen...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2012-07, Vol.22 (14), p.4719-4722
Main Authors: Chaturvedula, Prasad V., Pin, Sokhom, Tholady, George, Conway, Charlie M., Macor, John E., Dubowchik, Gene M.
Format: Article
Language:English
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
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Summary: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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2012.05.118