Discovery of Novel 1-Azoniabicyclo[2.2.2]octane Muscarinic Acetylcholine Receptor Antagonists
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- 作者：Dramane I. Lain ; Brent McCleland ; Sonia Thomas ; Christopher Neipp ; Brian Underwood ; Jeremy Dufour ; Katherine L. Widdowson ; Michael R. Palovich ; Frank E. Blaney ; James J. Foley ; Edward F. Webb ; Mark A.
- 刊名：Journal of Medicinal Chemistry
- 出版年：2009
- 出版时间：April 23, 2009
- 年：2009
- 卷：52
- 期：8
- 页码：2493-2505
- 全文大小：336K
- 年卷期：v.52,no.8(April 23, 2009)
- ISSN：1520-4804
文摘
A novel 4-hydroxyl(diphenyl)methyl substituted quinuclidine series was discovered as a very promising class of muscarinic antagonists. The structure−activity relationships of the connectivity of the diphenyl moiety to the quinuclidine core and around the ring nitrogen side chain are described. Computational docking studies using an homology model of the M3 receptor readily explained the observed structure−activity relationship of the various compounds. Compound 14o was identified as a very potent, slowly reversible M3 antagonist with a very long in vivo duration of bronchoprotection.