The discovery of highly potent CGRP receptor antagonists

Rational modification of a previously identified spirohydantoin lead structure has identified a series of potent spiroazaoxindole CGRP receptor antagonists. The azaoxindole was found to be a general replacement for the hydantoin that consistently improved in vitro potency. The combination of the ind...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2009, Vol.19 (1), p.214-217
Hauptverfasser:	Stump, Craig A., Bell, Ian M., Bednar, Rodney A., Bruno, Joseph G., Fay, John F., Gallicchio, Steven N., Johnston, Victor K., Moore, Eric L., Mosser, Scott D., Quigley, Amy G., Salvatore, Christopher A., Theberge, Cory R., Blair Zartman, C., Zhang, Xu-Fang, Kane, Stefanie A., Graham, Samuel L., Vacca, Joseph P., Williams, Theresa M.
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral Animals Biological and medical sciences Biological Availability CGRP Dogs Drug Discovery Headache Humans Indoles - chemical synthesis Indoles - pharmacology Macaca mulatta Medical sciences Migraine Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems Pharmacology. Drug treatments Receptors, Calcitonin Gene-Related Peptide - antagonists & inhibitors Spiro Compounds - chemical synthesis Spiro Compounds - pharmacology Structure-Activity Relationship
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Zusammenfassung:	Rational modification of a previously identified spirohydantoin lead structure has identified a series of potent spiroazaoxindole CGRP receptor antagonists. The azaoxindole was found to be a general replacement for the hydantoin that consistently improved in vitro potency. The combination of the indanylspiroazaoxindole and optimized benzimidazolinones led to highly potent antagonists (e.g., 25, CGRP K i = 40 pM). The closely related compound 27 demonstrated good oral bioavailability in dog and rhesus.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2008.10.106