New targets of pharmacotherapy of bronchial obstruction
Objective. To assess the prospects for scientific development of new classes of bronchodilators for respiratory diseases with obstructive syndrome, taking into account future molecular targets.
Materials and methods. The analysis of international English scientific information in the systems of surveys and search on the Internet for the last 5 years is carried out.
Results and discussion. Currently, there is an increasing interest in the development of new directions for pharmacological correction of the mechanisms of bronchial obstruction. The proposed international protocols are based on several groups of correctors: short-acting and prolonged-acting β-agonists, anticholinergics, methylxanthines, antileukotriene drugs and their combinations, but their safety limits their use in the age aspect. Therefore, the search for new targets for influencing bronchial tone remains relevant in respiratory pathology. There are nine potential new classes of bronchodilators that are being studied.
Selective phosphodiesterase inhibitors (PDE) were already known as roflumilast for the treatment of chronic obstructive pulmonary disease (COPD), but the genetic polymorphism of PDE isoenzymes, their different localization in subcellular microdomains, a complex signaling network and their selectivity for cyclic AMP or GMP all make it difficult to obtain and develop effective pharmacological action. Dual PDE3/PDE4 inhibitors are being developed taking into account that the PDE4 isoenzyme – the main one in most inflammatory cells involved in the pathogenesis of bronchial asthma (BA) and COPD, predominates in the smooth muscles (SM) of the bronchi; its inhibition leads to their relaxation, especially when interacting with stimulation of β2-adrenergic receptors. The double inhibition exposure can undoubtedly contribute to bronchodilator and anti-inflammatory activity. Evaluation of zardaverine, benzafentrin, tolafentrin and pumafentrin was carried out in volunteers, but without introduction into the clinic. Nevertheless, ensifenthrin, as the only dual PDE3/PDE4 inhibitor, has been proposed for the stage of clinical development in the treatment of BA, COPD, and cystic fibrosis, taking into account its high affinity for PDE3 (3440 times more against PDE4), mainly with a bronchodilatory effect, more effective in a synergistic combination with β2-agonists or anticholinergics. Dual inhibitors of PDE4/PDE7: these isozymes are expressed in immune cells through the control of cAMP, their double inhibition reduces bronchial hypersensitivity, production of proinflammatory interleukins in the experiment, which retains interest in a number of compounds – PDE4/PDE7 inhibitors. Dual PDE4/PDE5 inhibitors: especially attractive for their multilevel effect on bronchi, reduction of pulmonary hypertension and inflammation, lung remodeling. Thus, the combination of a PDE5 inhibitor (tadalafil) and PDE4 (roflumilast) improves these parameters in preclinical data, but their clinical development is questionable.
Agonists of bitter taste receptors – a group of 25 proteins – in addition to the tongue, are found in the respiratory epithelium and in the SM, where their three subtypes (10, 14 and 31) are highly expressed. The activation effect exceeds the relaxation of β-agonists by 2 times, with a high concentration of Ca2+ and relaxation, the search for agonists of this class against the background of a small amount of clinical data continues. Agonists of the E-prostanoid receptor-4 (PGE2): activation of the PGE2 receptor stimulates cAMP, the synthesis of several compounds of this type can relax the bronchi and in histamine spasm, can be interpreted as its key role, when administered orally, although it has not been tested in humans.
Inhibitors of Rh0 kinase: these protein kinases are highly represented in contractile SM, the RhoA/ROCK pathway regulates phosphatases of myosin light chains, two molecules have been proposed for clinical use – fasudil and ripasudil (Japan, China), but they have not yet been used in pulmonology for obstruction. Calcilytics: the G-protein receptor (guanine nucleotide) is associated with extracellular Ca2+, regulates the contraction in asthma and is elevated in sputum, also potential bronchodilators for the strategy. Among the new targets, PPAR-agonists should be named, although they affect lipid and glucose metabolism, are able to relax SM in asthma, their effects are debated. Agonists of the receptor relaxin-1 or -2 (studies of serelaxin) as a dilator and antifibrotic drug have demonstrated the generation of relaxing epithelial factors, but T1/2 only 10-20 min requires continuous infusion of 48 h, their conjugation with fatty acids creates a long-acting relaxin-2 analogue. NO donors can be useful, but the release of NO activates superoxide, induces tolerance, therefore these mechanisms are clarified in the experiment. Pepducins – lipidated peptides, through binding to G-proteins or arrestins, can also offer new strategies for signaling responses (biased agonists).
Conclusions. New possibilities for the development of bronchodilators are in the preclinical phase, but they can become an addition to the modern optimal therapy for bronchial obstruction.
This work is licensed under a Creative Commons Attribution 4.0 International License.