The identification of potent, orally bioavailable tricyclic CGRP receptor antagonists

A series of tricyclic CGRP receptor antagonists was optimized in order to improve oral bioavailability. Attenuation of polar surface area and incorporation of a weakly basic indoline nitrogen led to compound 5, a potent antagonist with good oral bioavailability in three species.

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2009-08, Vol.19 (16), p.4740-4742
Main Authors: Bell, Ian M., Bednar, Rodney A., Corcoran, Halea A., Fay, John F., Gallicchio, Steven N., Johnston, Victor K., Hershey, James C., Miller-Stein, Cynthia M., Moore, Eric L., Mosser, Scott D., Roller, Shane A., Salvatore, Christopher A., Theberge, Cory R., Wong, Bradley K., Blair Zartman, C., Kane, Stefanie A., Williams, Theresa M., Graham, Samuel L., Vacca, Joseph P.
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Biological and medical sciences
Biological Availability
Cell Line
CGRP
CGRP receptor antagonists
Dogs
Haplorhini
Heterocyclic Compounds, 3-Ring - administration & dosage
Heterocyclic Compounds, 3-Ring - chemistry
Heterocyclic Compounds, 3-Ring - pharmacokinetics
Humans
Medical sciences
Migraine
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Orally bioavailable
Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems
Pharmacology. Drug treatments
Rats
Receptors, Calcitonin Gene-Related Peptide - antagonists & inhibitors
Receptors, Calcitonin Gene-Related Peptide - metabolism
Spiro Compounds - administration & dosage
Spiro Compounds - pharmacokinetics
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Description
Summary:A series of tricyclic CGRP receptor antagonists was optimized in order to improve oral bioavailability. Attenuation of polar surface area and incorporation of a weakly basic indoline nitrogen led to compound 5, a potent antagonist with good oral bioavailability in three species.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2009.06.057