Bifunctional Compounds for the Treatment of COPD

Abstract

Chronic obstructive pulmonary disease is a disease of increasing incidence with a high unmet medical need, and new and more effective therapies are urgently required. Bronchodilators are central to symptom relief, and current therapeutic approaches include combinations of bronchodilators and anti-inflammatories often delivered by inhalation. Reviewed herein is an evolving paradigm in which two pharmacophores are covalently linked in a single molecule. The rationale for choosing the specific pairings and the advantages and challenges of this strategy are described. Examples include β agonists/muscarinic receptor antagonists, PDE4 inhibitors/muscarinic receptor antagonists, and β agonists/PDE4 inhibitors.

Introduction

Chronic obstructive pulmonary disease (COPD) is a chronic lung disease considered to be of high unmet medical need. The disease is characterized by airflow obstruction which is only partially reversible and is often progressive in nature.¹ The pulmonary symptoms are caused by pathological changes in the lungs particularly associated with small airways disease (obstructive bronchiolitis) and emphysema (alveolar tissue destruction). In addition to a compromised lung function, the disease may also be associated with chronic cough and sputum production and systemic components such as cachexia and depression. COPD is often associated with a number of comorbidities, most notably cardiovascular disease. Long-term cigarette smoking is the most common risk factor for COPD, but exposure of the lungs to other environmental noxious particles or gases has also been implicated. Such exposures are believed to contribute to a chronic inflammatory process that underlies the disease progression in predisposed individuals. Chronic inflammatory processes lead to structural remodeling including narrowing of the small airways and parenchymal destruction and loss of lung elastic recoil which causes the loss of lung function.¹ COPD is of increasing concern as a major public health problem with increasing rates of morbidity and mortality. It is projected to be the fourth major burden of disease and the third leading cause of death by 2030.(2), (3)

Inhaled bronchodilators are central to symptomatic relief in COPD and two major classes exist: β₂-adrenoceptor agonists (beta agonists) and anticholinergics (Fig. 14.1). Beta agonists act on β₂ receptors, which are seven-transmembrane domain-spanning G-protein-coupled receptors (GPCRs) situated on the smooth muscle cells in the airways. There are three subtypes of β adrenoceptors (β₁–β₃) which mediate the actions of adrenaline and noradrenaline. β₁ Receptors are present in the heart, and agonist binding can elicit both increases in heart rate and force of contraction. Functional selectivity of agonists for β₂ over β₁ receptors is therefore desirable as it could increase the therapeutic index for β₂-mediated bronchodilation over unwanted β₁-mediated increases in heart rate. β₂ Receptors are coupled to G_s proteins which activate adenylyl cyclase leading to formation of cyclic AMP. This elevation of intracellular cyclic AMP leads to relaxation of the smooth muscle and bronchodilation.⁵ Muscarinic receptors are seven-transmembrane-spanning GPCRs which mediate acetylcholine (ACh) signaling from the cell surface. There are a total of five muscarinic receptor subtypes (M₁–M₅) of which M₁, M₂, and M₃ are present in the lungs. M₁ and M₃ receptors are coupled to G_q proteins and utilize calcium as a second messenger through the action of phospholipase C and inositol triphosphate, whereas M₂ receptors are G_i linked which decreases cellular cyclic AMP levels and inhibits voltage-gated calcium channels.⁶ Muscarinic receptor antagonists act to block ACh signaling, thereby inhibiting the airway smooth muscle contraction which leads to bronchoconstriction. Muscarinic M₁ receptors are located on parasympathetic nerve ganglia and are responsible for facilitation of nerve transmission. M₂ receptors are located on postganglionic parasympathetic nerves and are the predominant receptor subtype on airway smooth muscle. The function of M₂ receptors is autoinhibitory which serves to maintain a tight regulation of ACh release. Muscarinic M₃ receptors are also located on airway smooth muscle cells and mediate airway smooth muscle contraction. Blockade of both M₁ and M₃ muscarinic receptor subtypes inhibits cholinergic-mediated bronchoconstriction. Presently, long-acting β₂ agonists (LABA) and long-acting muscarinic antagonists (LAMA) are used as the standard of care for symptomatic control in COPD.⁷

Recently, roflumilast, a novel oral anti-inflammatory agent that inhibits phosphodiesterase 4 (PDE4) enzyme activity, was approved for treatment of moderate and severe COPD associated with chronic bronchitis in patients at risk of exacerbations.⁸ While the clinical effect of roflumilast and related PDE4 inhibitors are as anti-inflammatory agents rather than as bronchodilators, PDE4 is present in airway smooth muscle cells and is responsible for the hydrolysis of cyclic AMP, which is important in bronchodilation. This compound has been shown to be effective in improving lung function as an add-on to the LABA, salmeterol and the LAMA, tiotropium bromide.⁹ To date, to the authors’ knowledge, no inhaled PDE4 inhibitors have progressed to registration trials in pulmonary disease. The pursuit of PDE4 subtype selective inhibitors has also been an area of high pharmaceutical industry interest as a way to achieve clinical efficacy and improve the systemic adverse effects associated with the compound drug class.¹⁰ There is also emerging preclinical evidence that dual PDE3/PDE4 inhibitors can combine bronchodilatory effects via direct PDE3 inhibition and act as an anti-inflammatory, which could be an alternative novel therapeutic approach.¹¹

Inhaled glucocorticoids have a broad range of anti-inflammatory actions through binding and activating cytosolic glucocorticoid receptor (GR)-α. Upon glucocorticoid binding with GR-α, the complex formed translocates to the cellular nucleus where it can bind with a glucocorticoid response element in the promoter region of target genes to modulate gene expression. Glucocorticoids can mediate both gene repression (transrepression) and gene induction (transactivation) to exert their anti-inflammatory effects.¹² The level of efficacy achieved by inhaled glucocorticoids in COPD remains a controversial topic but they do improve symptoms, lung function, and reduce exacerbations in more severe patients.¹ The combination of an inhaled β₂ agonist and glucocorticoid therapies has been shown to be superior to individual treatments alone with respect to lung function and health status as well as reducing disease-related exacerbations in patients with moderate to severe disease.¹³

Combination products consisting of two medications and two modes of action have been highly successful. Seretide®/Advair®, a combination of the LABA, salmeterol, and the inhaled corticosteroid, fluticasone propionate, used for both COPD and asthma, was the prescription drug with the third highest sales in 2010.¹⁴ Coadministration of two mechanistically distinct chemical entities is one approach for combination drug therapy, but it is also possible to use a “bifunctional compound,” also referred as a “dual selective pharmacology molecule,” which is a single chemical entity with two distinct pharmacophores covalently bonded. While the design seems conceptually simple, connection points and linkers must be chosen carefully, as the choices can significantly impact the activity of either pharmacophore. The compounds, being the combination of two pharmacophores, tend to have high molecular weights, but the net molecular size may offer an advantage as an inhaled therapeutic, because it can result in greater lung retention and lower oral bioavailability, thereby reducing systemic exposure and related downstream toxicology issues.¹⁵ Due to the size of the molecules and the inherent flexibility of many of the linkers, it may also be a challenge to obtain crystalline compounds for development. However, a single chemical entity with two activities would offer multiple advantages, including matched pharmacokinetics, simplified formulation, and simplified clinical development.¹⁶ Significantly, there is potential for a combination product consisting of a novel bifunctional compound and a separate additional medication in a single device to deliver three mechanisms. The alternative development and engineering of an inhaler capable of delivering these separate drugs, with unique disease-related mechanisms, is yet to be realized.

Described herein are novel bifunctional molecules designed through linking of pharmacophores of approved therapeutic targets: muscarinic antagonists, β agonists, and PDE4 inhibitors. Additional combination examples, such as neutrophil elastase inhibitor/muscarinic antagonist¹⁷ or epithelial sodium channel inhibitor/β agonist,¹⁸ have also been disclosed.