1. Discovery of novel and long acting muscarinic acetylcholine receptor antagonists.
- Author
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Jin J, Wang Y, Shi D, Wang F, Davis RS, Jin Q, Fu W, Foley JJ, Webb EF, Dehaas CJ, Berlanga M, Burman M, Sarau HM, Morrow DM, Rao P, Kallal LA, Moore ML, Rivero RA, Palovich M, Salmon M, Belmonte KE, and Busch-Petersen J
- Subjects
- Animals, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Bronchoconstriction drug effects, Drug Evaluation, Preclinical methods, Guinea Pigs, Mice, Rats, Tyrosine pharmacology, Muscarinic Antagonists pharmacology, Phenylurea Compounds pharmacology, Quaternary Ammonium Compounds pharmacology, Tyrosine analogs & derivatives
- Abstract
High throughput screening and subsequent optimization led to the discovery of novel quaternary ammonium salts as highly potent muscarinic acetylcholine receptor antagonists with excellent selectivity. Compounds 8a, 13a, and 13b showed excellent inhibitory activity and long duration of action in bronchoconstriction in vivo models in two species via intranasal or intratracheal administration. The novel inhaled muscarinic receptor antagonists are potentially useful therapeutic agents for the treatment of chronic obstructive pulmonary disease and other bronchoconstriction disorders.
- Published
- 2008
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