ABSTRACT
Exploration of multiple regions of a bi-aryl amine template led to the identification of highly potent M(3) muscarinic acetylcholine receptor antagonists such as 14 (pA(2)=11.0) possessing good sub-type selectivity for M(3) over M(2). The structure-activity relationships (SAR) and optimization of the bi-aryl amine series are described.
Subject(s)
Amines/chemical synthesis , Chemistry, Pharmaceutical/methods , Receptor, Muscarinic M3/antagonists & inhibitors , Amides/chemistry , Amines/pharmacology , Asthma/drug therapy , Drug Design , Electrons , Humans , Inhibitory Concentration 50 , Kinetics , Models, Chemical , Molecular Structure , Pulmonary Disease, Chronic Obstructive/drug therapy , Receptor, Muscarinic M3/chemistry , Structure-Activity RelationshipABSTRACT
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.
