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-trif
详细信息 查看全文
- 作者：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. W
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：November 15, 2007
- 年：2007
- 卷：50
- 期：23
- 页码：5564 - 5567
- 全文大小：53K
- 年卷期：v.50,no.23(November 15, 2007)
- ISSN：1520-4804
文摘
Calcitonin gene-related peptide (CGRP) has been implicatedin the pathogenesis of migraine. Herein we describe optimization ofCGRP receptor antagonists based on an earlier lead structure containinga (3R)-amino-(6S)-phenylcaprolactam core. Replacement of the phenylimidazolinone with an azabenzimidazolone gave stable derivatives withlowered serum shifts. Extensive SAR studies of the C-6 aryl moietyrevealed the potency-enhancing effect of the 2,3-difluorophenyl group,and trifluoroethylation of the N-1 amide position resulted in improvedoral bioavailabilities, ultimately leading to clinical candidate 38 (MK-0974).