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-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.
Department of Molecular Sciences, Bristol-Myers Squibb R&D, 5 Research Parkway, Wallingford, CT 06492, USA. prasad.chaturvedula@bms.com
Prasad V
PV
Chaturvedula
Sokhom
S
Pin
George
G
Tholady
Charlie M
CM
Conway
John E
JE
Macor
Gene M
GM
Dubowchik
D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D015195:Drug Design; D006860:Hydrogen Bonding; D015394:Molecular Structure; D013141:Spiro Compounds / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D013141:Spiro Compounds