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Long-acting muscarinic antagonists for the treatment of chronic obstructive pulmonary disease

Muscarinic acetylcholine receptor antagonists, particularly of the M3 subtype, are useful therapeutics as bronchodilators in chronic obstructive pulmonary disease (COPD). The first long-acting muscarinic antagonist, tiotropium bromide (Spiriva®), was launched in 2002 and has since become established as the gold-standard muscarinic antagonist for the treatment of COPD. This review will survey the preclinical profiles of tiotropium and nine inhaled development candidates as well as literature reports of other preclinical compounds specifically designed as inhaled antimuscarinic agents for the treatment of COPD. The design strategies employed lay behind three common principles: high potency and slow reversibility at the M3 receptor and low systemic exposure. In addition to their effectiveness as bronchodilators, the differentiation of these agents in the clinic may be linked to their potential to be utilized in combination with other therapeutics. In the long term, the emerging knowledge around the role of muscarinic antagonists in the inflammation and remodeling of the airways may also help in discriminating them.