The discovery of highly potent CGRP receptor antagonists

• Published in: Bioorganic & medicinal chemistry letters Vol. 19; no. 1; pp. 214 - 217
• Main Authors: 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: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 2009; Elsevier
• Subjects: 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; Headache; CGRP; Migraine; Embryo; Monkey; Kidney; Pain; Structure activity relation; Primates; Antagonist; CGRP receptor; Neurological disorder; Chemical synthesis; Dog; Human; Fissipedia; Carnivora; Indan derivatives; Bioavailability; Hydantoins; In vitro; Spiran; Vertebrata; Mammalia; Cell line; Benzimidazole derivatives; Animal; Carboxamide; Pharmacokinetics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2008.10.106

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.