1. Discovery of Novel and Long Acting Muscarinic Acetylcholine Receptor Antagonists
- Author
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Palovich Michael R, Miriam Burman, Edward F. Webb, Roderick S. Davis, Henry M. Sarau, Yonghui Wang, Wei Fu, Dwight M. Morrow, Jian Jin, Feng Wang, Qi Jin, Kristen E. Belmonte, Parvathi Rao, Michael L. Moore, Manuela Berlanga, James J. Foley, Chris J. Dehaas, Michael Salmon, Ralph A. Rivero, Lorena A. Kallal, Jakob Busch-Petersen, and Dongchuan Shi
- Subjects
medicine.drug_class ,Bronchoconstriction ,Guinea Pigs ,Drug Evaluation, Preclinical ,Muscarinic Antagonists ,Pharmacology ,Inhibitory postsynaptic potential ,Mice ,In vivo ,Bronchodilator ,Drug Discovery ,Muscarinic acetylcholine receptor ,medicine ,Animals ,Acetylcholine receptor ,Chemistry ,Phenylurea Compounds ,Antagonist ,Bridged Bicyclo Compounds, Heterocyclic ,Rats ,Quaternary Ammonium Compounds ,Biochemistry ,Tyrosine ,Molecular Medicine ,Nasal administration ,medicine.symptom - 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