Developing inhaled drugs for respiratory diseases: A medicinal chemistry perspective

doi:10.1016/j.drudis.2021.09.005

Drug Discovery Today

Volume 27, Issue 1, January 2022, Pages 134-150

https://doi.org/10.1016/j.drudis.2021.09.005 Get rights and content

Abstract

Despite the devastating impact of many lung diseases on human health, there is still a significant unmet medical need in respiratory diseases, for which inhaled delivery represents a crucial strategy. More guidance on how to design and carry out multidisciplinary inhaled projects is needed. When designing inhaled drugs, the medicinal chemist must carefully balance the physicochemical properties of the molecule to achieve optimal target engagement in the lung. Although the medicinal chemistry strategy is unique for each project, and will change depending on multiple factors, such as the disease, target, systemic risk, delivery device, and formulation, general guidelines aiding inhaled drug design can be applied and are summarised in this review.

Introduction

The drug discovery community has developed many guidelines to help medicinal chemists with oral drug design, including defining optimal physicochemical property space to help maximise exposure and minimise safety concerns and attrition in downstream toxicology studies.1, 2 These guiding principles are well known across the industry but, by contrast, medicinal chemists are, in general, less familiar with how to effectively prosecute inhaled delivery projects. In this review, we discuss the key principles that guide inhalation by design (see Glossary) and the challenges that must be overcome in the design and development of inhaled medicines. We also explain why a broad multidisciplinary team of drug discovery experts is required to undertake this task effectively.

The ongoing Coronavirus 2019 (COVID-19) pandemic has brought into focus the devastating impact of lung diseases, with scientists around the world urgently seeking new therapies. Repurposing of known anti-inflammatory and antiviral drugs for inhaled delivery is one of the strategies being pursued to overcome the cytokine storm caused by COVID-19 and maximise exposure at the primary site of infection.3, 4 The biggest selling respiratory drugs are currently targeted toward asthma and chronic obstructive pulmonary disease (COPD), servicing a predicted global market of more than US$56 billion by 2025,⁵ and representing a significant portion of the drug market.

Currently, only a limited number of mechanisms of action are represented within marketed inhaled drugs, with established treatments being primarily targeted at anti-inflammatory and bronchodilatory mechanisms. Inhaled corticosteroids (ICS), such as budesonide, together with long-acting β2-agonists (LABA), such as salmeterol, and long-acting muscarinic antagonists (LAMA), such as tiotropium, form the mainstay of treatments for asthma and COPD. However, new mechanisms are emerging, largely as add-on therapies to manage exacerbations that can be severe and require hospitalisation. These incidences of respiratory failure, often driven by infection, can lead to increased patient mortality in the absence of an effective treatment. Examples of add-on therapies include Boehringer Ingelheim’s marketed oral PDE4 inhibitor roflumilast as well as PI3Kδ inhibitors (e.g., GSK’s nemiralisib) and JAK inhibitors that are in clinical and preclinical development. In addition, some biologics are starting to impact asthma therapy, such as AstraZeneca’s anti-interleukin (IL)-5 receptor α monoclonal antibody benralizumab and Genentech-Novartis’s anti-IgE omalizumab; however, they are expensive, usually dosed intravenously, and target small patient populations with more severe disease.

Although there are several marketed treatments for asthma and, to a lesser extent, COPD, there remains a significant unmet clinical need, particularly in lung diseases, such as bronchiectasis, idiopathic pulmonary fibrosis (IPF), pulmonary arterial hypertension (PAH), and respiratory infections, such as COVID-19 and those driving exacerbations; therefore, inhaled delivery represents a crucial strategy in current drug discovery.

Section snippets

Advantages of inhaled delivery

Inhaled drug delivery offers many potential benefits for the treatment of respiratory diseases, and has resulted in this route of delivery becoming the standard choice in the treatment of lung diseases, such as asthma and COPD. The main potential advantages of inhaled delivery are summarised below (Fig. 1a).

The first, and most obvious, benefit of inhalation is the direct delivery of the drug to the site of action. Avoiding common barriers to therapeutic efficacy, such as poor absorption from

Challenges to inhaled delivery

Although there are many advantages of dosing by inhalation, there are also multiple challenges to be overcome in the development of a molecule intended for inhaled delivery that require a team of multidisciplinary scientists to address.

The respiratory system as a target is a complex organ, with a heterogeneous structure and multiple lung-specific pharmacokinetic (PK) processes, all of which need to be considered when developing an inhaled drug (Fig. 1a).6, 16 Depending on the device and the

Key considerations for an inhaled candidate profile

From a medicinal chemistry point of view, it is important to recognise that the key features that characterise an inhaled candidate profile are significantly different from an oral profile. Some of the desired properties also differ depending upon whether the compound is to be designed for once- or twice-daily chronic dosing, or whether it is intended for the rapid treatment of acute exacerbations. In this review, we focus mainly on the profile of dry powder candidates designed for chronic

Considerations for human dose predictions

It is important to note that unbound drug concentrations at the pharmacological target site cannot be easily measured or predicted in inhaled projects.²³ Measured drug concentrations in the lung after inhaled delivery are not the effective concentration but comprise an insoluble (inactive) and soluble (available) dose fraction. The objective is to maintain an effective concentration gradient of free drug over the target site for a suitable duration. Early in an inhaled drug discovery project,

Medicinal chemistry considerations for in vivo dosing in preclinical models

There are several different formulations and routes of administrations that can be used to dose inhaled compounds for preclinical in vivo evaluation. This is an important factor to consider because the choice made can significantly impact lung deposition. As medicinal chemists, it is key to work closely with in vivo biologists and formulation scientists to find the optimal delivery strategy, based on the physicochemical properties and PK profile of the lead compounds and the intended route of

Medicinal chemistry considerations for in vivo dosing to patients

It is also important to know at an early stage of an inhaled drug discovery program which delivery device is going to be used in the clinic. Device selection will impact the desired properties of the compounds under investigation and the medicinal chemistry strategy chosen to optimise the chemical series. By contrast, device selection will depend on the disease state and patient acceptability. Therefore, medicinal chemists need to be aware of the clinical considerations at the outset of a

Medicinal chemistry strategies in inhaled programs

The chemical design strategies in an inhaled program will depend on many factors, such as the nature of the target (intracellular versus extracellular, receptor versus enzyme), the mode of action (agonist versus antagonist, activator versus inhibitor), the desired duration of action and the means of achieving it (PK versus binding kinetics, limited solubility versus soluble compounds), the desired onset of action, and the systemic risk (is a level of systemic ‘spill over’ tolerated?).

Although

Strategies to minimise side effects: Limiting systemic exposure

Low free plasma levels can be achieved through: (i) exquisite potency to drive down the dose requirement; (ii) low oral bioavailability; and (iii) high clearance from the systemic circulation (e.g., insertion of soft spot/conjugation).

Among them, high clearance and low absorption are the most common. Use of pro/ante-drugs is less common but has benefits and has been proven successful in some instances.

ICSs exert anti-inflammatory effects by binding to glucocorticoid receptors (GR) in the lung

Strategies to increase lung retention

One of the greatest challenges of an inhaled project is achieving adequate retention of the compound in the respiratory tract. Prolonged target tissue retention is difficult to achieve because of the mucociliary clearance mechanisms described earlier. In particular, the physiology of the lung contributes to the challenges of lung retention. The lung has a very large surface area, thin alveolar and capillary membranes, with an average thickness of <0.5 mm, and is a highly perfused organ,

Impact of solubility and dissolution rate on lung retention

Increased lung retention of a compound can be achieved through lowering solubility and/or dissolution rate. The plot in Fig. 3a⁴⁰ shows how, after inhaled delivery for a range of chemically diverse compounds, decreased aqueous solubility or dissolution rate in simulated lung fluid (SLF) correlates with a prolonged rat lung PK half-life.

Medicinal chemistry design can also be aided by pharmaceutics because mechanical processes can be exploited to modulate dissolution rate. The latter can be

Impact of permeability on lung retention

Reducing the permeability of a compound can slow its absorption through the lung, which can in turn help to increase lung retention. The low permeability of inhaled drugs, such as LAMAs and LABAs, has been associated with their long lung retention,⁶ whereas Novartis recently showed how a series of inhaled PDGFR inhibitors for the treatment of PAH was optimised for duration of action via increased basicity and reduced permeability.⁴⁵ Fig. 3c shows an inversely proportional correlation between

Impact of basicity on lung retention

Increasing basicity is a driver of lung retention.50, 51 Basicity and lipophilicity both influence the volume of distribution (V_d), driving partitioning into lung tissue, and this reservoir can be a way of slowing down the removal of a drug from the lung. Basic compounds (pK_a > 8) can be trapped within acidic organelles, called lysosomes, which are prevalent in lung tissue, thus creating a depot from which the drug is slowly released over an extended period of time.52, 53 Uptake of basic

Impact of receptor kinetics on lung retention

Slow kinetics is a valid approach for inhaled delivery because of the high local concentrations that are able to drive the drug onto the receptor. Slow dissociation of a molecule from its receptor can result in a long duration of action; however, designing compounds with slow off-rate kinetics can be challenging. Investigating drug–target residence time can help to understand disconnects between PK and PD data: compounds with slow receptor dissociation kinetics can display a pronounced PD

Mechanism-specific approaches to increase lung retention

Lung retention can also be enhanced through other strategies. Generally, such approaches are serendipitous and highly specific, and cannot be broadly applied as a medicinal chemistry strategy. Nevertheless, two such strategies are worthy of mention.

The first example is the lipid conjugation mechanism that is observed for budesonide (Fig. 2, compound 10). Budenoside is an ICS used for the treatment of asthma and COPD, and is retained in the lung through lipid conjugation via esterification of

Pharmaceutics: Solid form developability requirements and solid form analyses

The solid form properties of a compound can influence many aspects of its chemical and biological profile, such as solubility, stability, dissolution rate, lung permeability, PK profile, efficacy, and duration of action.

The crystalline structure, such as a needle shape, can also be a cause of irritancy and is an additional factor that needs consideration during development of an inhaled clinical candidate. Morphology can sometimes be controlled through optimisation of the crystallisation

Inhaled drug discovery: Historical perspective and outlook

Considerable progress has been made in the development of drugs for inhaled delivery and several trends have appeared in the drug discovery literature.

Sometimes, divergent medicinal chemistry strategies have been used to approach the same therapeutic target in respiratory diseases.81, 82, 83 For example, PF-03715455 and AZD7624 are both p38 inhibitors that were designed for the treatment of COPD. However, PF-03715455 (Fig. 2, compound 13) has high polarity and lipophilicity (cLogP = 6.6) and

Acknowledgement

The authors would like to thank David Clark, Andrew Carr and Mike Briggs (Charles River Laboratories, UK) for their support and insightful feedback during the manuscript preparation.

Glossary

Ante-drug (or soft drug): active drugs designed to undergo biotransformation to a readily excretable inactive form with the aim of minimising systemic side effects and increase the therapeutic index.
Bronchiectasis: a long-term condition in which the airways of the lungs become abnormally widened, leading to a build-up of excess mucus and increased risk of lung infections.
Bronchoalveolar lavage (BAL): diagnostic procedure by which a saline solution is injected into the bronchial and alveolar spaces to

Elisa Pasqua received her PhD degree in organic chemistry from the University of Glasgow, where she worked in the Marquez group on the total synthesis of natural products. She spent her postdoctoral years at the Institute of Cancer Research (London), where she worked on the development of small-molecule inhibitors of the HSF1 stress pathway activation in cancer, under the supervision of Keith Jones. In 2017, Elisa joined Charles River Laboratories (CRL), where she is a group leader. At CRL, she

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Citation Excerpt :
The inhaled treatment for respiratory diseases is favorable as respiratory delivery can ensure a higher concentration of a drug in the lung and blood at lower doses than its oral doses meaning minimal to no side effects with better therapeutic outcomes (Khadka et al., 2021). For example, inhaled 100–200 μg of salbutamol is therapeutically equivalent to 2–4 mg of oral salbutamol, so less chance of side effects associated with this drug (Pasqua et al., 2022). Rapid onset of action is a matter of concern for severe COVID-19 patients as a sudden respiratory crisis may happen and such issues can be overcome by inhaled treatment.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent responsible for the COVID-19 pandemic, has outspread at full tilt across the world. Although several effective vaccines continue to be deployed, reliable antiviral treatments have yet to be developed against this disease. Currently, available therapeutics for COVID-19 include repurposed, and a few novel drugs. Many drugs have been promising in preclinical studies, but a majority of these drugs have shown little or no efficacy in clinical studies. One of the major reasons is the insufficient drug concentration in the lung, the primary target site of infection for SARS-CoV-2, from the administration of drugs through oral or intravenous routes. Higher effective doses administered through these routes could also lead to adverse side effects. For this reason, inhaled treatments are being tested as an efficient approach for COVID-19, allowing lower doses of drugs ensuring higher concentrations of the drug(s) in the lung. The inhaled treatment combining two or more antiviral drugs will increase potency and reduce the possibility of selecting for SARS-CoV-2 variants with reduced drug susceptibility. Finally, the appropriate drug combination needs to be delivered using a suitable system. Here, we review the current treatment for COVID-19 and their limitations, discussing the advantages of mono and combinational inhaled therapy with a brief outline of the recently reformulated anti-SARS-CoV-2 agents as inhaled formulations. The selection of appropriate delivery devices for inhalation and associated key considerations including the formulation challenges are also discussed.
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Nicole Hamblin holds a first-class honours degree and a PhD from Oxford University and is currently head of chemistry & DMPK, Early Discovery at CRL, overseeing more than 150 scientists engaged in drug discovery contract research. Before joining CRL, Nicole spent 20 years at GlaxoSmithKline (GSK), delivering multiple clinical candidates and leading progression of respiratory asset nemiralisib into Phase II trials. In 2014, she won the Royal Society of Chemistry Capps Green Zomaya Award for medicinal chemistry, and was appointed a Fellow of the Royal Society of Chemistry in 2017.

Christine Edwards received a PhD in Chemistry from the University of Newcastle upon Tyne, where she worked on resistance-modifying inhibitors of DNA repair. After two postdoctoral years in Marburg and Newcastle, she became a lecturer in organic and medicinal chemistry at the University of Essex, specialising in photodynamic therapy. In 2002, she joined Argenta Discovery as a senior medicinal chemist and now holds the position of Group Leader within CRL. She has 18 years’ experience in the design of molecules for inhaled delivery and has contributed to the discovery of multiple development candidates for the treatment of respiratory diseases.

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Keynote (green)Developing inhaled drugs for respiratory diseases: A medicinal chemistry perspective

Abstract

Introduction

Section snippets

Advantages of inhaled delivery

Challenges to inhaled delivery

Key considerations for an inhaled candidate profile

Considerations for human dose predictions

Medicinal chemistry considerations for in vivo dosing in preclinical models

Medicinal chemistry considerations for in vivo dosing to patients

Medicinal chemistry strategies in inhaled programs

Strategies to minimise side effects: Limiting systemic exposure

Strategies to increase lung retention

Impact of solubility and dissolution rate on lung retention

Impact of permeability on lung retention

Impact of basicity on lung retention

Impact of receptor kinetics on lung retention

Mechanism-specific approaches to increase lung retention

Pharmaceutics: Solid form developability requirements and solid form analyses

Inhaled drug discovery: Historical perspective and outlook

Acknowledgement

Glossary

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Int J Pharm

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Bioorg Med Chem Lett

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Biomed Pharmacother

Pulm Pharmacol Ther

Facts, patterns, and principles in drug discovery: appraising the Rule of 5 with measured physicochemical data

J Med Chem

Improving drug candidates by design: a focus on physicochemical properties as a means of improving compound disposition and safety

Chem Res Toxicol

Drug repurposing in the COVID-19 era: insights from case studies showing pharmaceutical peculiarities

Pharmaceutics

Inhaled therapy in respiratory disease: the complex interplay of pulmonary kinetic processes

Can Respir J

Inhaler devices for the treatment of asthma and chronic obstructive airways disease (COPD)

Qual Saf Health Care

Pulmonary drug delivery. Part I: physiological factors affecting therapeutic effectiveness of aerosolized medications

Br J Clin Pharmacol

Non-invasive delivery strategies for biologics

Nat Rev Drug Discov

Single inhaler LABA/LAMA for COPD

Front Pharmacol

Advances in asthma and COPD treatment: combination therapy with inhaled corticosteroids and long-acting beta 2-agonists

Curr Pharm Des

Evaluating triple ICS/LABA/LAMA therapies for COPD patients: a network meta-analysis of ETHOS, KRONOS, IMPACT, and TRILOGY studies

Expert Rev Respirat Med

The inhalation of drugs: advantages and problems

Respir Care

Inhalation drug delivery devices: technology update

Med Devices (Auckl)

Pharmacokinetic/pharmacodynamic evaluation of inhalation drugs: application to targeted pulmonary delivery systems

Expert Opin Drug Deliv

Short-term effects of inhaled salbutamol on autonomic cardiovascular control in healthy subjects: a placebo-controlled study

Br J Clin Pharmacol

Management of airway mucus hypersecretion in chronic airway inflammatory disease: Chinese expert consensus (English edition)

Int J Chron Obstruct Pulmon Dis

Gaining the upper hand on pulmonary drug delivery

J Pharmacovigil

Dry powder inhalers: an overview

Respir. Care

Pulmonary drug metabolism, clearance, and absorption

Keynote (green)
Developing inhaled drugs for respiratory diseases: A medicinal chemistry perspective