Novel CGRP receptor antagonists from central amide replacements causing a reversal of preferred chirality

A previously utilized quinoline-for-N-phenylamide replacement strategy was employed against a central amide in a novel class of CGRP receptor antagonists. A unique and unexpected substitution pattern was ultimately required to maintain reasonable affinity for the CGRP receptor, while at the same tim...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2010-11, Vol.20 (22), p.6827-6830
Main Authors: Wood, Michael R., Schirripa, Kathy M., Kim, June J., Bednar, Rodney A., Fay, John F., Bruno, Joseph G., Moore, Eric L., Mosser, Scott D., Roller, Shane, Salvatore, Christopher A., Vacca, Joseph P., Selnick, Harold G.
Format: Article
Language:English
Subjects:
Amides - chemistry
Amides - pharmacology
Antagonist
Biological and medical sciences
Calcitonin gene-related peptide
CGRP
Medical sciences
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems
Pharmacology. Drug treatments
Receptors, Calcitonin Gene-Related Peptide - antagonists & inhibitors
Stereoisomerism
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Summary:A previously utilized quinoline-for-N-phenylamide replacement strategy was employed against a central amide in a novel class of CGRP receptor antagonists. A unique and unexpected substitution pattern was ultimately required to maintain reasonable affinity for the CGRP receptor, while at the same time predicting acceptable heterocycle positioning for related analogs. Subsequently, specific quinoline and naphthyridine compounds were prepared which supported these structural predictions by displaying CGRP binding affinities in the 0.037–0.15nM range.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2010.08.105