Potent, orally bioavailable calcitonin gene-related peptide receptor antagonists for the treatment of migraine: discovery of N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1- (2,2,2-trifluoroethyl)azepan-3-yl]-4- (2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin- 1-yl)piperidine-1-carboxamide (MK-0974).

Abstract

Calcitonin gene-related peptide (CGRP) has been implicated in the pathogenesis of migraine. Herein we describe optimization of CGRP receptor antagonists based on an earlier lead structure containing a (3R)-amino-(6S)-phenylcaprolactam core. Replacement of the phenylimidazolinone with an azabenzimidazolone gave stable derivatives with lowered serum shifts. Extensive SAR studies of the C-6 aryl moiety revealed the potency-enhancing effect of the 2,3-difluorophenyl group, and trifluoroethylation of the N-1 amide position resulted in improved oral bioavailabilities, ultimately leading to clinical candidate 38 (MK-0974).

• Authors: Daniel V Paone, Anthony W Shaw, Diem N Nguyen, Christopher S Burgey, James Z Deng, Stefanie A Kane, Kenneth S Koblan, Christopher A Salvatore, Scott D Mosser, Victor K Johnston, Bradley K Wong, Cynthia M Miller-Stein, James C Hershey, Samuel L Graham, Joseph P Vacca, Theresa M Williams
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 50 Issue 23 Pg. 5564-7 (Nov 15 2007) ISSN: 0022-2623 [Print] United States
• PMID: 17929795 (Publication Type: Journal Article)

Chemical References

• Azepines
• Calcitonin Gene-Related Peptide Receptor Antagonists
• Imidazoles
• telcagepant

Topics

• Administration, Oral
• Animals
• Azepines (chemical synthesis, pharmacokinetics, pharmacology)
• Biological Availability
• Caco-2 Cells
• Calcitonin Gene-Related Peptide Receptor Antagonists
• Cell Membrane Permeability
• Dogs
• Humans
• Imidazoles (chemical synthesis, pharmacokinetics, pharmacology)
• Macaca mulatta
• Migraine Disorders (drug therapy)
• Rats
• Regional Blood Flow (drug effects)
• Skin (blood supply)
• Stereoisomerism
• Structure-Activity Relationship