Discovery of (3-endo)-3-(2-cyano-2,2-diphenylethyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane bromide as an efficacious inhaled muscarinic acetylcholine receptor antagonist for the treatment of COPD |
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| Authors: | Zehong Wan Dramane I Laine Hongxing Yan Chongjie Zhu Katherine L Widdowson Peter T Buckley Miriam Burman James J Foley Henry M Sarau Dulcie B Schmidt Edward F Webb Kristen E Belmonte Michael Palovich |
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| Institution: | Respiratory Centre of Excellence for Drug Discovery, Research and Development, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, PO Box 1539, King of Prussia, PA 19406, USA |
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| Abstract: | Design and syntheses of a novel series of muscarinic antagonists are reported. These efforts have culminated in the discovery of (3-endo)-3-(2-cyano-2,2-diphenylethyl)-8,8-dimethyl-8-azoniabicyclo3.2.1]octane bromide (4a) as a potent and pan-active muscarinic antagonist as well as a functionally active compound in a murine model of bronchoconstriction. The compound has also displayed pharmacokinetic characteristics suitable for inhaled delivery. |
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