Discovery of biphenyl piperazines as novel and long acting muscarinic acetylcholine receptor antagonists.
Jin J, Budzik B, Wang Y, Shi D, Wang F, Xie H, Wan Z, Zhu C, Foley JJ, Webb EF, Berlanga M, Burman M, Sarau HM, Morrow DM, Moore ML, Rivero RA, Palovich M, Salmon M, Belmonte KE, Lainé DI.
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.