Design and synthesis of potent antagonists containing rigid spirocyclic privileged structures for the CGRP receptor.
| Autor: | Chaturvedula PV; Department of Molecular Sciences, Bristol-Myers Squibb R&D, 5 Research Parkway, Wallingford, CT 06492, USA. prasad.chaturvedula@bms.com, Pin S, Tholady G, Conway CM, Macor JE, Dubowchik GM |
|---|---|
| Jazyk: | angličtina |
| Zdroj: | Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2012 Jul 15; Vol. 22 (14), pp. 4719-22. Date of Electronic Publication: 2012 Jun 09. |
| DOI: | 10.1016/j.bmcl.2012.05.118 |
| Abstrakt: | 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. (Copyright © 2012 Elsevier Ltd. All rights reserved.) |
| Databáze: | MEDLINE |
| Externí odkaz: |
|
Full Text from ScienceDirect