MK2: a novel molecular target for anti-inflammatory therapy

Background: Mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2) is activated upon stress by p38 MAPK. MK2 is stimulated in a wide range of inflammatory conditions and its catalytic activity is required for cytokine production, cell migration and is a potential drug target for inflammatory diseases. Disruption of MK2 leads to a reduction in TNF-α production. MK2-mediated pro-inflammatory cytokine production has been demonstrated in several inflammatory conditions where TNF-α plays a role. Objective/methods: We discuss the development of specific MK2 inhibitors for the treatment of inflammatory diseases. Results/conclusion: Inhibition of the p38 MAPK pathway may have therapeutic uses for inflammatory diseases. However, blocking p38 MAPK activation in vivo is not advisable due to toxicity, significant off-target effects, and lack of oral bioavailability. This concern may be countered by the use of MK2 inhibitors that can dissect the pathways downstream of p38 without affecting additional cellular functions.     

The p38 MAPK inhibitors for the treatment of inflammatory diseases and cancer

Background: The p38 mitogen-activated protein kinase (MAPK) is activated by various pro-inflammatory and stressful stimuli. Mounting evidence suggests that the p38 MAPK signaling cascade is involved in various biological responses other than inflammation such as cell proliferation, differentiation, apoptosis and invasion, suggesting that the p38 MAPK can serve as a potential therapeutic target for the treatment of not only inflammatory diseases but also cancer. Methods: The unique characteristics of p38 MAPK are summarized with regard to activation and function of p38 MAPK signaling cascades. We then discuss the involvement of p38 MAPK in diseases and the implications of the possible therapeutic use of p38 MAPK inhibitors. The p38 MAPK inhibitors that have been used in the in vitro/in vivo systems as well as in the clinical trials are summarized. Results/conclusion: The p38 MAPK plays an important role in key cellular processes related to inflammation and cancer. Understanding the signal transduction mechanisms and gene regulation by p38 MAPK provides useful information in the development of p38 MAPK inhibitors with therapeutic benefits with reduced side effects. In this review, we summarize and present the list of p38 MAPK inhibitors in in vitro/in vivo studies as well as in clinical trials.     

Respivert’s multikinase inhibitors,an evaluation of WO2014033446 to WO2014033449

These four patent applications all claim that N-aryl-N′-pyrazol-5-yl urea derivatives , related to RV-568, which are inhibitors of p38, Syk and Src kinases. All four applications claim their use in the treatment of inflammatory diseases, notably asthma and chronic obstructive pulmonary disease. The four applications are primarily differentiated by the claimed substitution of the pyrazole ring. This is accompanied by differential kinase specificity profiles. Many of the exemplified compounds show reduced potency as p38 inhibitors but high potency as inhibitors of Syk and/or Src kinases.     

p38 MAPK inhibitors: a patent review (2012 – 2013)

Introduction: The p38 MAPK is a ubiquitous target in the research-based pharmaceutical industry. It plays a decisive role in the regulation of the production of proinflammatory cytokines. Since novel biological therapies have revolutionized the treatment of chronic inflammatory diseases, an intensive global search is underway for small molecules for the same application.

Areas covered: Herein, the patents and the corresponding publications of international companies, which focus on the development and identification of a new generation of small-molecule p38 inhibitors, are summarized.

Expert opinion: The most promising approach is the development of linear binders, which induce a glycine flip at Gly110 of the kinase hinge region by a carbonyl oxygen atom of the respective ligand. The major focus of the patent works was the application of molecules in new indications. Previous applications were in the treatment of rheumatoid arthritis; currently, there are several new applications, including pulmonary diseases, cancer and Alzheimer's disease. Targeting p38 upstream kinases and downstream effectors has also proved to be a very promising step in the development of more effective inhibitors. A further trend is drug combination, applied to a wide range of indications, such as chronic obstructive pulmonary disease and cancer.     

Targeting mitogen-activated protein kinases for asthma

Allergic asthma is a chronic airway inflammatory disorder attributable to T-helper 2 cell responses together with other inflammatory cells such as mast cells, B cells and eosinophils, and pro-inflammatory cytokines and chemokines. Mitogen-activated protein kinase (MAPK) signaling cascades have been shown to be important in the differentiation, activation, proliferation, degranulation and migration of various immune cells, and airway smooth muscle and epithelial cells. In mammal, MAPK signaling modules are divided into at least 3 groups: extracellular signal-regulated kinase (ERK), p38 MAPK, and c-Jun NH2-terminal kinase (JNK). Each MAPK module plays a discrete yet complementary role in accentuating allergic airway inflammation. Cumulative evidence reveals potential anti-inflammatory activities of MAPK inhibitors in a variety of in vitro models of inflammation. Recently, the anti-inflammatory effects of MAPK kinase inhibitor (U0126), p38 MAPK inhibitors (SB239063 and respirable p38alpha MAPK antisense oligonucleotide) and JNK inhibitor (SP600125) have been demonstrated in in vivo animal models of asthma. Development of inhibitors targeting at MAPK could be an attractive strategy for the treatment of asthma.     

Neutrophil elastase inhibitors: a patent review and potential applications for inflammatory lung diseases (2010 – 2014)

Introduction: The proteolytic activity of neutrophil elastase (NE) not only destroys pathogens but also degrades host matrix tissues by generating a localized protease–antiprotease imbalance. In humans, NE is well known to be involved in various acute and chronic inflammatory diseases, such as chronic obstructive pulmonary disease, emphysema, asthma, acute lung injury, acute respiratory distress syndrome and cystic fibrosis. The regulation of NE activity is thought to represent a promising therapeutic approach, and NE is considered as an important target for the development of novel selective inhibitors to treat these diseases.

Areas covered: This article summarizes and analyzes patents on NE inhibitors and their therapeutic potential based on a review of patent applications disclosed between 2010 and 2014.

Expert opinion: According to this review of recent NE inhibitor patents, all of the disclosed inhibitors can be classified into peptide- and non-peptide-based groups. The non-peptide NE inhibitors include heterocyclics, uracil derivatives and deuterium oxide. Among the heterocyclic analogs, derivatives of pyrimidinones, tetrahydropyrrolopyrimidinediones, pyrazinones, benzoxazinones and hypersulfated disaccharides were introduced. The literature has increasingly implicated NE in the pathogenesis of various diseases, of which inflammatory destructive lung diseases remain a major concern. However, only a few agents have been validated for therapeutic use in clinical settings to date.     

Investigational p38 inhibitors for the treatment of chronic obstructive pulmonary disease

Introduction: The p38 protein kinases, in particular p38α and p38β, regulate the production of multiple inflammatory mediators. Consequentially, considerable effort has been focused on trying to develop p38 inhibitors for the treatment of inflammatory diseases. Some 20 p38 inhibitors have progressed to clinical development, mostly for the treatment of rheumatoid arthritis, but with little success. Increasingly, interest has turned to their use in other indications and notably chronic obstructive pulmonary disease (COPD).

Areas covered: In this review, the author discusses the eight p38 inhibitors that have been clinically evaluated. Acumapimod is the only one of four orally delivered inhibitors that remains in active development while Phase II results of PH-797804 and losmapimod are compared. The activity of two inhibitors designed for inhaled delivery, RV-568 and PF-03715455, is compared but little is known about AZD-7624 or the discontinued GSK-610677.

Expert opinion: Results from animal models provide a clear rationale for developing p38 inhibitors for COPD, and appear to be (partially) validated by the efficacy seen with PH-797804 and losmapimod. Inhaled delivery provides the opportunity to enhance p38 inhibition in the lung while reducing unwanted systemic effects of p38 inhibition. Validation of this hypothesis should come from the results of the recently completed Phase II study with RV-568.     

Discovery of naphthyl‐N‐acylhydrazone p38α MAPK inhibitors with in vivo anti‐inflammatory and anti‐TNF‐α activity

Protein kinases constitute attractive therapeutic targets for development of new prototypes to treat different chronic diseases. Several available drugs, like tinibs, are tyrosine kinase inhibitors; meanwhile, inhibitors of serine/threonine kinases, such as mitogen‐activated protein kinase (MAPK), are still trying to overcome some problems in one of the steps of clinical development to become drugs. So, here we reported the synthesis, the in vitro kinase inhibitory profile, docking studies, and the evaluation of anti‐inflammatory profile of new naphthyl‐N‐acylhydrazone derivatives using animal models. Although all tested compounds ( 3a–d ) have been characterized as p38α MAPK inhibitors and have showed in vivo anti‐inflammatory action, LASSBio‐1824 ( 3b ) presented the best performance as p38α MAPK inhibitor, with IC₅₀ = 4.45 μm , and also demonstrated to be the most promising anti‐inflammatory prototype, with good in vivo anti‐TNF‐α profile after oral administration.     

Dry powder inhalers in COPD,lung inflammation and pulmonary infections

Introduction: The number of pulmonary diseases that are effectively treated by aerosolized medicine continues to grow.

Areas covered: These diseases include chronic obstructive pulmonary disease (COPD), lung inflammatory diseases (e.g., asthma) and pulmonary infections. Dry powder inhalers (DPIs) exhibit many unique advantages that have contributed to the incredible growth in the number of DPI pharmaceutical products. To improve the performance, there are a relatively large number of DPI devices available for different inhalable powder formulations. The relationship between formulation and inhaler device features on performance of the drug–device combination product is critical. Aerosol medicine products are drug–device combination products. Device design and compatibility with the formulation are key drug–device combination product aspects in delivering drugs to the lungs as inhaled powders. In addition to discussing pulmonary diseases, this review discusses DPI devices, respirable powder formulation and their interactions in the context of currently marketed DPI products used in the treatment of COPD, asthma and pulmonary infections.

Expert opinion: There is a growing line of product options available for patients in choosing inhalers for treatment of respiratory diseases. Looking ahead, combining nanotechnology with optimized DPI formulation and enhancing device design presents a promising future for DPI development.     

Therapeutic Potential of p38 MAP Kinase Inhibition in the Management of Cardiovascular Disease

p38 mitogen-activated protein kinases (p38 MAPKs) are key signalling molecules that regulate cellular behavior in response to environmental stresses. They regulate pro-inflammatory cytokines and therefore p38 MAPKs are implicated in the pathogenesis of many inflammatory-driven conditions, including atherosclerosis. Therapeutic inhibition of p38 MAPKs to attenuate inflammation has been the focus of comprehensive research in the last 2 decades, following the discovery of p38α as the molecular target of pyrindinyl imidazole compounds, which suppress the cytokines tumor necrosis factor-α and interleukin-1. The potential of p38 MAPK inhibitors was initially explored within archetypal inflammatory conditions such as rheumatoid arthritis and Crohn’s disease, but early studies demonstrated poor clinical efficacy and unacceptable side effects. Subsequent clinical trials evaluating different p38 MAPK inhibitor compounds in disease models such as chronic obstructive pulmonary disease (COPD) and atherosclerosis have shown potential clinical efficacy. This review aims to provide succinct background information regarding the p38 MAPK signaling pathway, a focus of p38 MAPKs in disease, and a brief summary of relevant pre-clinical studies. An update of human clinical trial experience encompassing a clinically orientated approach, dedicated to cardiovascular disease follows. It provides a current perspective of the therapeutic potential of p38 MAPK inhibitors in the cardiovascular domain, including safety, tolerability, and pharmacokinetics.     

Berberine regulates pulmonary inflammatory microenvironment and decreases collagen deposition in response to bleomycin-induced pulmonary fibrosis in mice

The purpose of this study was to explore the protective effect and potential mechanism of berberine on bleomycin (BLM)-induced fibrosis after lung injury in conjunction with network pharmacology. Berberine and pulmonary fibrosis prediction targets were collected for Gene Ontology (GO) functional analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and so forth. A single intranasal dose of BLM (2.5 mg/kg) was administered to establish a model of fibrosis after lung injury, and berberine (50 mg/kg) was administered intraperitoneally daily for treatment. Network pharmacology results suggested that the mitogen-activated protein kinase (MAPK) signalling pathway may be a potential mechanism of berberine in delaying pulmonary fibrosis. The results of animal experiments showed that compared with the BLM group, after 14 days of berberine treatment, lung inflammatory cell aggregation was reduced and the expression levels of tumour necrosis factor-α (TNF-α), interleukin (IL)-8 and IL-6 were down-regulated in mice (p < 0.05); after 42 days of berberine treatment, the expression levels of transforming growth factor (TGF)-β1, platelet-derived growth factor-AB (PDGF-AB), hydroxyproline (HYP) and α-smooth muscle actin (α-SMA) were significantly down-regulated (p < 0.05), and the expression levels of total p38 MAPKα and p38 MAPKα (pT180/Y182) were down-regulated also (p < 0.05), inhibited collagen production and deposition, and increased the survival rate of mice to 70%. In conclusion, berberine attenuated inflammation mice, inhibited collagen production and showed some anti-pulmonary fibrosis potential in the MAPK signalling pathway.     

Inhibitors of cathepsin C (dipeptidyl peptidase I)

Importance to the field: Cathepsin C (dipeptidyl peptidase I) plays a key role in the activation of several degradative enzymes linked to tissue destruction in inflammatory diseases. Thus, cathepsin C inhibitors could potentially be effective therapeutics for the treatment of such diseases as chronic obstructive pulmonary disease and cystic fibrosis.

Areas covered in this review: Although this article focuses on cathepsin C inhibitor patents, the journal literature concerning small molecule inhibitors of the enzyme is also covered comprehensively (1981 – 2009).

What the reader will gain: It is our aim to give the reader a complete overview of the cathepsin C inhibitor chemotypes that have been disclosed to date. In addition, key biological data have been included for both irreversible and reversible inhibitors.

Take home message: All known cathepsin C inhibitors are believed to have a covalent interaction with the Cys-234 residue of the enzyme. The electrophilic and sometimes peptidic nature of these molecules is associated with poor metabolic stability and is also a potential safety concern. Thus, overcoming developability issues is a serious hurdle for these compounds and there can be little doubt that this is the principal reason why no cathepsin C inhibitors appear to have reached clinical development so far.     

Therapeutic potential of non-peptide chymase inhibitors

Background: α-Chymase may have a role in the pathophysiology of certain cardiac diseases (myocardial infarction, hypertrophy, fibrosis, and heart failure), vascular diseases (atherosclerosis, proliferation), skin diseases, and many fibrotic conditions. Inhibitors of chymase may be useful in these conditions. Objectives: The aim was to briefly review the pathophysiological role of chymase, and to discuss in more detail the published literature (patent and journal) relating to non-peptide chymase inhibitors. Results: The review showed that many selective inhibitors of chymase have been patented, and some show good selectivity and potency. Some of the chymase inhibitors have been shown to be effective in animal models of heart disease, vascular disease, fibrosis, and adhesion. None of the chymase inhibitors have entered clinical trial to date. Conclusions: Of the potential clinical uses of chymase inhibitors, inhibition of fibrosis seems to be the most marked effect, and suitable for advancement. It is possible that chymase inhibitors may never become first-line treatment for any disease or condition, but they may become important adjuvant treatment for the fibrosis associated with many diseases and conditions.     

Comparative amino acid decomposition analysis of potent type I p38α inhibitors

Background and purpose of the study

p38α is a member of mitogen-activated protein kinases (MAPK) considered as a prominent target in development of anti-inflammatory agents. Any abnormality in the phosphorylation process leads to the different human diseases such as cancer, diabetes and inflammatory diseases. Several small molecule p38α inhibitors have been developed up to now. In this regard, structural elucidation of p38 inhibitors needs to be done enabling us in rational lead development strategies.

Methods

Various interactions of three potent inhibitors with p38α active site have been evaluated in terms of binding energies and bond lengths via density function theory and MD simulations.

Results

Our comparative study showed that both ab initio and MD simulation led to the relatively similar results in pharmacophore discrimination of p38α inhibitors.

Conclusion

The results of the present study may find their usefulness in pharmacophore based modification of p38α inhibitors.     

Novel 8-benzoylimidazo[1,2-a] pyridin-5-one mitogen-activated protein kinase inhibitors

A series of p38 mitogen-activated protein kinase (MAPK) inhibitors based upon an 8-benzoylimidazo[1,2-a]pyridin-5-one scaffold are claimed. Their use for the treatment of inflammatory disease, especially chronic obstructive pulmonary disease, is also claimed. This represents a relatively unusual use of MAPK inhibitors. The scaffold employed represents a novel variant on the arylazole scaffold commonly employed in designing MAPK inhibitors.     

Annotated Patent Selections

Inflammatory conditions such as rheumatoid arthritis (RA) and other autoimmune diseases represent a very active area of research for the development of novel therapeutics. In the past few years, the research focus of many pharmaceutical companies and other organisations has resulted in the identification of various novel biological targets for the development of new therapies for the treatment of inflammatory diseases such as RA. This has resulted in the identification of biological agents such as infliximab (Remicade^®, Centocor, Inc.), etanercept (Enbrel^®,Immunex Corp.), adalimumab (Humira^®,Abbott Lab.) and kineret (Anakinra^®, Amgen, Inc.) that affect the TNF-α or IL1 associated pathways, for the treatment of RA and other inflammatory diseases such as psoriasis and inflammatory bowel disease (IBD). Ongoing research continues to expand the application of these agents for additional therapeutic use. In addition to the biological agents above, cyclooxygenase-2 (COX-2) inhibitors such as rofecoxib (Vioxx^®, Merck &; Co., Inc.) and celecoxib (Celebrex^®, Pharmacia) have also shown some efficacy for the treatment of RA. The approval of these agents for the treatment of RA has provided a validation of the role of TNF-α, IL-1 and COX-2 in the pathogenesis of RA. Although the biologicals and COX-2 inhibitors are effective, they are however limited in that they modulate a single cytokine or pathway. It is recognised that the alternate pathway delineated by p38 mitogen-activated protein kinase (MAPK) provides for a more combinatorial path for treatment of RA, as an inhibitor of p38 MAPK would not only affect TNF-α, IL-1 and other related cytokines, but also the expression of COX-2. The efforts to develop small molecule agents for p38 MAPK have not yet yielded an agent ready for the market, but several inhibitors are presently under investigation in clinical trials. While details of these studies have yet to be formally reported, two recently published studies have evaluated the effect of p38 inhibitors on the suppression of pro-inflammatory cytokines and other markers of inflammation in healthy human volunteers exposed to endotoxaemia, caused by exposure to lipopolysaccharide (LPS) [1,2].     

Inhibitors of stress-activated protein/mitogen-activated protein kinase pathways

The importance of stress-activated protein/mitogen-activated protein kinase (SAP/MAPK) pathway signalling (involving c-Jun-N-terminal kinase [JNK], extracellular signal-regulated kinase [ERK] and p38 kinase) in normal cellular proliferation, differentiation and programmed cell death has led to significant recent advances in our understanding of the role of SAP/MAPK signaling in inflammatory disorders such as arthritis and cardiovascular disease, cancer, and pulmonary and neurogenerative diseases. The discovery that several natural products such as resveratrol, tangeretin and ligustilide non-specifically inhibit SAP/MAPK signalling in vitro should now be logically extended to studies designed to determine how agents in these natural products regulate SAP/MAPK pathways in animal models of disease. A new generation of small-molecule SAP/MAPK inhibitors that demonstrate increasing specificity for each of the JNK, ERK and p38 kinase isoforms has shown promise in animal studies and could eventually prove effective for treating human diseases. Several of these compounds are already being tested in human subjects to assess their oral bioavailability, pharmacokinetics and toxicity.     

Targeting 5-lipoxygenase-activating protein in asthma and chronic obstructive pulmonary disease

Introduction: In asthma and chronic obstructive pulmonary disease (COPD), there is an unmet therapeutic need for the anti-inflammatory therapies, and the identification of therapeutic targets and potent corresponding therapies is necessary. Although inhaled corticosteroids and leukotriene modifiers are most effective in asthma they are still not always capable of appropriately controlling the disease. In COPD, the therapeutic gap is even larger because inhaled corticosteroids and other anti-inflammatory therapies are not beneficial in all disease subsets.

Areas covered: The role of the 5-lipoxygenase-activating protein (FLAP) in generating proinflammatory molecules such as leukotrienes is discussed, highlighting, in particular, its potential as a therapeutic target in asthma and COPD. The preclinical data on FLAP inhibitors are discussed. The clinical data on the FLAP inhibitors investigated so far for these diseases are analyzed.

Expert opinion: FLAP inhibitors have emerged during the past decade as a promising therapeutic class in asthma and COPD, but there exists only a limited amount of data supporting their efficacy in these diseases. This might be due to the fact that the development of some of the molecules discussed was abandoned. Such therapies might be of particular interest in COPD and in asthma-COPD overlap syndrome.