Chapter 3 - Multivalent Dual Pharmacology Muscarinic Antagonist and β2 Agonist (MABA) Molecules for the Treatment of COPD
Introduction
Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide [1]. This persistent and partially irreversible respiratory disease is characterized by progressive airflow limitation and is commonly associated with long-term cigarette smoking. Airflow limitation is caused by a combination of small airway disease (obstructive bronchiolitis), parenchymal destruction (emphysema) and inflammation. The global initiative for chronic obstructive lung disease (GOLD) has categorized COPD into four stages (1 = mild, 2 = moderate, 3 = severe and 4 = very severe) based on lung function [2]. Severe lung dysfunction and chronic inflammation in COPD patients leads to airway remodelling and is associated with systemic co-morbidities including skeletal muscle wasting, cachexia and cardiovascular disease [3]. An additional disease classification system known as the BODE (body-mass index, airflow obstruction, dysponea and exercise capacity) index takes into account some of these non-pulmonary co-morbidities in the assessment of disease severity [4].
Inhaled bronchodilators are the cornerstone for the pharmacological management of COPD and are recommended at all stages of the disease. The most frequently used inhaled bronchodilators are muscarinic acetylcholine receptor (mAChR) antagonists and β2-adrenergic receptor (β2-AR) agonists. Once-daily tiotropium (1) [5] is currently the only approved long-acting muscarinic antagonist (LAMA) while aclidinium (2) [6] (a LAMA-dosed bid), glycopyrronium bromide (3) [7] and GSK-573719 [8] are in advanced clinical trials. The long-acting nature of these therapies serves to control COPD symptoms, while also increasing patient compliance [9] through their convenient dosing regimens (Fig. 3.1).
Prescribed long-acting β2-AR agonists (LABAs) include formoterol, its active component arformoterol (4) [10] and salmeterol (5) [11], [12]. These drugs are approved for twice-daily dosing regimens, while new once-daily ‘ultra’ LABAs such as indacaterol (6) [13] (now approved in the USA and Europe), vilanterol (7) [14] and olodaterol (8) [15] (in late-stage clinical trials) are seen as the next generation of LABA therapy (Fig. 3.2).
The combination of a mAChR antagonist and β2-AR agonist (BA) has proven an effective treatment option for patients with moderate to severe COPD. Preclinical data support the hypothesis that these receptors in the lung act through complementary pathways [16]. Co-administration of a mAChR antagonist and BA has demonstrated greater efficacy than either class of bronchodilator alone [17], [18]. Combivent® is the only marketed product that is formulated in a single inhalation device and consists of a short-acting mAChR antagonist (SAMA) ipratropium (9) [19], and a short-acting β2-AR agonist (SABA), albuterol (10) [20]. However, due to the short-lasting activities of ipratropium (9) and albuterol (10), Combivent® requires four times daily dosing. Though a successful means of controlling the symptoms of COPD, the multiple doses per day required when using Combivent® are inconvenient and may impact compliance (Fig. 3.3).
A number of clinical trials in COPD patients have shown that combining a LAMA (tiotropium (1)) with a LABA (salmeterol (5) or formoterol (4)) improves efficacy without additive side effects [21], [22], [23], [24]. However, in these studies, the muscarinic antagonist (MA) and BAs were dosed separately, either once or twice a day, respectively. Owing to mismatched pharmacokinetics and pharmacodynamics of these molecules, these combinations do not maximize the net efficacy of both mechanisms for patients nor eliminate the need for multiple inhalers and, therefore, may impact patient compliance. Several novel LAMA + LABA fixed-dose combinations, such as QVA 149 (glycopyrronium bromide (3) + indacaterol (6)) [7], are in development as once-daily bronchodilators [25]. The results from these studies are encouraging, but compliance could still be an issue if patients are prescribed an inhaled corticosteroid (ICS) in addition to the LAMA + LABA inhaler to enable ‘triple therapy’.
The principal aims in managing COPD are to achieve optimal control of all symptoms and to improve a patient's quality of life. In cases of severe COPD, the addition of an ICS is recommended. Several studies have demonstrated an additional benefit for COPD patients receiving triple therapy (LAMA + LABA/ICS) in COPD, including improved lung function, reduction in exacerbations and an overall improved quality of life in comparison to monotherapy [26], [27]. Therefore, the ideal combination could be a triple LAMA/LABA/ICS co-formulation. However, this currently presents an unachievable technical challenge [28]. One strategy to overcome these difficulties is to design a single molecule with dual pharmacology (muscarinic antagonist and β2-AR agonist, MABA) that could be more readily co-formulated with an ICS. The attractiveness of the MABA concept for treatment of COPD has led to the development of several MABA candidates, the most advanced being GSK-961081 (TD-5959) [29].
Section snippets
Multivalency background
Theravance employed a multivalent design strategy to develop a potent ligand exhibiting MA and BA activities. A multivalent ligand is predicted to exhibit higher receptor affinity than its monovalent fragments. The valency of a ligand refers to the number of distinct binding interactions it makes with a target protein [30]. Theravance's definition of multivalent binding is the simultaneous interaction of multiple ligand-binding motifs with adjacent concavities on a receptor or adjacent
Evaluating Inhaled Bronchodilator Therapies in Animal Models
Animal models of bronchoconstriction have led to the discovery of novel MA and BA bronchodilators that treat human respiratory disorders. These models include the whole-body plethysmograph model that measures pulmonary resistance and dynamic compliance in anesthetized, spontaneously breathing animals [41], [42], [43], [44], the non-invasive penH plethysmograph model that assesses respiratory function by measuring enhanced pause in conscious animals [42], [45], [46], the Konzett–Rõssler model
Design considerations for inhaled drugs
At first glance, the inhaled route of administration might seem more attractive to the medicinal chemist with the restraints of oral drug design no longer relevant in order to achieve site of action delivery. However, many other factors must be considered, and in practice, the challenges are redistributed rather than reduced.
There have been several strategies described to minimize systemic exposure and potential side effects of inhaled drugs. The local delivery of the drugs offers a significant
Conclusions
The complementary nature of the mAChR bronchoconstriction and β2-AR bronchodilation pathways has attracted considerable effort in the discovery of dual pharmacology MABA compounds. The opportunity to achieve greater bronchodilation than with either mechanism alone has resulted in several companies following the precedent set by Theravance. Through a ‘linked’ or ‘conjugated pharmacophore’ approach, several new linkers and attachment points (on the muscarinic pharmacophore) have been discovered
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