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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Bibliographische Detailangaben
Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2009-08, Vol.19 (16), p.4740-4742
Hauptverfasser:	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:	Artikel
Sprache:	eng
Schlagworte:	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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Beschreibung
Zusammenfassung:	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