Potent oxadiazole CGRP receptor antagonists for the potential treatment of migraine

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 4; pp. 1368 - 1372
• Main Authors: Nichols, Paula L., Brand, Jonathan, Briggs, Michael, D’Angeli, Mathilde, Farge, Jennifer, Garland, Stephen L., Goldsmith, Paul, Hutchings, Rio, Kilford, Ian, Li, Ho Y., MacPherson, David, Nimmo, Fiona, Sanderson, Francis Dominic, Sehmi, Sanjeet, Shuker, Nicola, Skidmore, John, Stott, Michael, Sweeting, Jennifer, Tajuddin, Hasmi, Takle, Andrew K., Trani, Giancarlo, Wall, Ian D., Ward, Robert, Wilson, David M., Witty, David
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.02.2010; Elsevier
• Subjects: Administration, Oral; Animals; Biological and medical sciences; CGRP; CGRP receptor antagonists; Drug Design; Medical sciences; Migraine; Migraine Disorders - drug therapy; Models, Molecular; Molecular Structure; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Oxadiazoles; Oxadiazoles - chemical synthesis; Oxadiazoles - chemistry; Oxadiazoles - therapeutic use; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Rats; Receptors, Calcitonin Gene-Related Peptide - antagonists & inhibitors; Oxadiazoles; CGRP receptor antagonists; CGRP; Migraine; Intravenous administration; Rat; Antimigrainous agent; Rodentia; Oral administration; Aminoether; Biological activity; Vertebrata; Mammalia; Pain; Imidazopyridine derivatives; Animal; Chlorine Organic compounds; Piperidine derivatives; Oxadiazole derivatives; Antagonist; CGRP receptor; Pharmacokinetics; Chemical synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.01.012

Using a pharmacophore model, based on known CGRP receptor antagonists, a novel series of oxadiazole CGRP receptor antagonists has been identified and the subsequent optimisation to enhance both potency and bioavailability is presented. A pharmacophore model was built, based on known CGRP receptor antagonists, and this was used to aid the identification of novel leads. Analogues were designed, modelled and synthesised which incorporated alternative ‘LHS’ fragments linked via either an amide or urea to a privileged ‘RHS’ fragment commonly found in CGRP receptor antagonists. As a result a novel series of oxadiazole CGRP receptor antagonists has been identified and the subsequent optimisation to enhance both potency and bioavailability is presented.