Discovery of biphenyl piperazines as novel and long acting muscarinic acetylcholine receptor antagonists.

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 M(3) over M(2) and M, 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 arc potentially useful therapeutic agents for the treatment of chronic obstructive pulmonary disease.