3-Phenyl-5-isothiazole carboxamides with potent mGluR1 antagonist activity
详细信息 查看全文
- 作者：Matthew J. Fisher ; fisher_matthew_j@lilly.com ; Ryan T. Backer ; Vanessa N. Barth ; Kim E. Garbison ; Joseph M. Gruber ; Beverly A. Heinz ; Smriti Iyengar ; Sean P. Hollinshead ; Anne Kingston ; Steven L. Kuklish ; Linglin Li ; Eric S. Nisenbaum ; Steven C. Peters ; Lee Phebus ; Rosa Maria A. Simmons ; Ellen van der Aar
- 关键词：mGluR1 ; Receptor occupancy ; Formalin model
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2012
- 出版时间：1 April, 2012
- 年：2012
- 卷：22
- 期：7
- 页码：2514-2517
- 全文大小：763 K
文摘
The disclosed 3-phenyl-5-isothiazole carboxamides are potent allosteric antagonists of mGluR1 with generally good selectivity relative to the related group 1 receptor mGluR5. Pharmacokinetic properties of a member of this series (1R,2R)-N-(3-(4-methoxyphenyl)-4-methylisothiazol-5-yl)-2-methylcyclopropanecarboxamide (14) are good, showing acceptable plasma and brain exposure after oral dosing. Oral administration of isothiazole 14 gave robust activity in the formalin model of persistent pain which correlated with CNS receptor occupancy.