Long acting muscarinic antagonists for the treatment of chronic obstructive pulmonary disease: a review of current and developing drugs

ABSTRACT

Introduction: Long acting muscarinic receptor antagonists (LAMA) reverse airflow obstruction by antagonizing para-sympathetic bronchoconstricting effects within the airways. For years, tiotropium, has been the cornerstone LAMA for chronic obstructive pulmonary disease (COPD) management. Recently, new agents, aclidinium bromide, glycopyrronium bromide, and umeclidinium bromide, have been developed and introduced into clinical practice.

Areas covered: This article reviews the clinical efficacy and adverse effects of currently available LAMAs in COPD treatment as well as developing LAMAs in early clinical trials and preclinical studies (V0162, TD-4208, CHF 5407, AZD9164, AZD8683, bencycloquidium). In addition, a new class of molecule that combines muscarinic antagonist and β2-adrenergic properties (MABA) is described and current developmental progress discussed (GSK-961081, THRX-200495).

Expert opinion: Future key areas for developing drugs for the management of COPD include prolonged duration of action, optimal delivery systems, synergistic combinations with other drugs, maximization of benefits and minimization of adverse effects. The development of new LAMA and MABA molecules provides exciting progress towards simpler and more effective COPD management.

KEYWORDS:

• AZD8683
• AZD9164
• Bencycloquidium
• CHF 5407
• TD-4208
• chronic obstructive pulmonary disease
• long acting muscarinic receptor antagonist (LAMA)
• muscarinic antagonist and B2-agonist (MABA)
• V0162

Article highlights

• LAMAs function by preferentially binding to muscarinic M3 receptors interrupting signal transduction pathway involving the Gαq protein and phospholipase C. This pathway leads to multiple mechanisms for phosphorylation of myosin light chains and bronchial smooth muscle contractions thus causing bronchodilation.

• Tiotropium, aclidinium bromide, umeclidinium bromide and glycopyrronium bromide are currently available for clinical use and have been shown to improve lung function, quality of life and reduce exacerbations in individuals with COPD.

• Comparison studies reveal no clinically significant differences between the currently available LAMAs

• Developing LAMAs may provide potentially equal or even greater clinical benefits with fewer adverse effects

• MABAs are novel molecules that have significant potential clinical efficacy due to their ability to target both muscarinic and beta-2 adrenergic receptors

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded