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Discovery of Biphenyl Piperazines as Novel and Long Acting Muscarinic Acetylcholine Receptor Antagonists

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posted on 09.10.2008 by Jian Jin, Brian Budzik, Yonghui Wang, Dongchuan Shi, Feng Wang, Haibo Xie, Zehong Wan, Chongye Zhu, James J. Foley, Edward F. Webb, Manuela Berlanga, Miriam Burman, Henry M. Sarau, Dwight M. Morrow, Michael L. Moore, Ralph A. Rivero, Michael Palovich, Michael Salmon, Kristen E. Belmonte, Dramane I. Lainé
A series of novel biphenyl piperazines was discovered as highly potent muscarinic acetylcholine receptor antagonists via high throughput screening and subsequent optimization. Compound 5c with respective 500- and 20-fold subtype selectivity for M3 over M2 and M1 exhibited excellent inhibitory activity and long duration of action in a bronchoconstriction in vivo model in mice via intranasal administration. The novel inhaled mAChR antagonists are potentially useful therapeutic agents for the treatment of chronic obstructive pulmonary disease.

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