Dual PDE3/4 and PDE4 Inhibitors: Novel Treatments For COPD and Other Inflammatory Airway Diseases

Selective phosphodiesterase (PDE) 4 and dual PDE3/4 inhibitors have attracted considerable interest as potential therapeutic agents for the treatment of respiratory diseases, largely by virtue of their anti‐inflammatory (PDE4) and bifunctional bronchodilator/anti‐inflammatory (PDE3/4) effects. Many of these agents have, however, failed in early development for various reasons, including dose‐limiting side effects when administered orally and lack of sufficient activity when inhaled. Indeed, only one selective PDE4 inhibitor, the orally active roflumilast‐n‐oxide, has to date received marketing authorization. The majority of the compounds that have failed were, however, orally administered and non‐selective for either PDE3 (A,B) or PDE4 (A,B,C,D) subtypes. Developing an inhaled dual PDE3/4 inhibitor that is rapidly cleared from the systemic circulation, potentially with subtype specificity, may represent one strategy to improve the therapeutic index and also exhibit enhanced efficacy versus inhibition of either PDE3 or PDE4 alone, given the potential positive interactions with regard to anti‐inflammatory and bronchodilator effects that have been observed pre‐clinically with dual inhibition of PDE3 and PDE4 compared with inhibition of either isozyme alone. This MiniReview will summarize recent clinical data obtained with PDE inhibitors and the potential for these drugs to treat COPD and other inflammatory airways diseases such as asthma and cystic fibrosis.     

Development of agents for the treatment of systemic sclerosis

Systemic sclerosis (SSc) is a multisystem connective tissue disease characterised clinically by fibrosis and ischaemic atrophy. Internal organ involvement can be life-threatening. Although there are effective treatments for some of the organ-based manifestations of SSc, for example proton-pump inhibitors for upper gastrointestinal disease, no drug has so far been proven to modify the underlying disease process. Our increased understanding of the pathogenesis of SSc, which involves a complex interplay between excessive collagen production, vascular abnormalities and immune dysfunction, is directing development of drugs which hold promise as 'disease-modifying' agents. Some of the drugs under investigation for the treatment of SSc have already been used in other conditions which 'overlap' with SSc, for example primary pulmonary hypertension. Conversely, it is to be hoped that in the future, drugs shown to be effective in SSc might prove beneficial for other fibrotic diseases.     

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.     

Genus Bupleurum: a review of its phytochemistry, pharmacology and modes of action

Objectives Radix Bupleuri represents one of the most successful and widely used herbal drugs in Asia for treatment of many diseases over the past 2000 years. Thorough studies have been carried out on many species of this genus and have generated immense data about the chemical composition and corresponding biological activity of extracts and isolated secondary metabolites. In this work, we review the chemistry and pharmacology of the genus Bupleurum and explore the relationships between the pharmacological effects and the chemical composition of these drugs. Key findings Early studies on the genus Bupleurum had focused only on the traditional uses of the plants in the treatment of inflammatory disorders and infectious diseases. After chemical profiling, several groups of secondary metabolites were characterized with relevant biological activity: triterpene saponins (saikosaponins), lignans, essential oils and polysaccharides. As a result, present interest is now focused on the bioactivity of the isolated triterpene saponins acting as immunomodulatory, anti‐inflammatory and antiviral agents, as well as on the observed ant‐iulcer activity of the polysaccharides and anti‐proliferative activity of different lignans. Many saikosaponins exhibited very potent anti‐inflammatory, hepatoprotective and immunomodulatory activities both in vivo and in vitro. Conclusions Further investigations and screenings are required to explore other Bupleurum species, to evaluate the clinical safety and possible interactions with other drugs or herbs. Standardization of Bupleuri extracts is crucial for them being integrated into conventional medicine due to large chemical and biological variations between different species and varieties.     

Anti‐inflammatory effects of Artemisia princeps in antigen‐stimulated T cells and regulatory T cells

Objectives The aim was to investigate the anti‐inflammatory effects of Artemisia princeps extract on the activity of anti‐CD3/CD28‐stimulated CD4⁺CD25^‐ T cells and antigen‐expanded regulatory T cells. Methods CD4⁺CD25^‐ T cells were activated with coated anti‐CD3 and anti‐CD28 and cultured in the presence or absence of various concentrations of A. princeps extract. The cultures were pulsed on Day 6 with [³H]thymidine and, after harvesting the cells, [³H] thymidine incorporation was measured. For analysis of interleukin‐2 and interferon‐γ secreted from CD4⁺CD25^‐ T cells, culture supernatants were collected on Days 2 and 6. For the analysis of interleukin‐10 secreted from the CD4⁺CD25^‐ T cells and expanded regulatory T cells, supernatants were collected after 2 and 7 days, respectively. Cytokine levels were determined using an enzyme‐linked immunosorbent assay. Potential medicinal components of the A. princeps extract were determined using gas chromatography–mass spectrometry. Key findings A. princeps (30 μg/ml) effectively suppressed proliferation of CD4⁺CD25^‐ T cells that were stimulated with anti‐CD3/CD28 without causing cytotoxicity in spleen cells incubated under conditions lacking antigen stimulation. A. princeps inhibited production of the pro‐inflammatory cytokines interleukin‐2 and interferon‐γ in anti‐CD3/CD28‐stimulated CD4⁺CD25^‐ T cells. Also, the extract slightly increased production of the anti‐inflammatory cytokine interleukin‐10 in these cells. In regulatory T cells expanded by anti‐CD3/CD28, A. princeps increased production of interleukin‐10 and Foxp3. Conclusions The results suggest that A. princeps may be useful in the treatment of autoimmune diseases and organ transplantation rejection by inhibiting proliferation of inflammatory T cells, suppressing inflammatory processes in antigen‐stimulated CD4⁺CD25^‐ T cells and increasing activity of expanded regulatory T cells.     

Histone deacetylase inhibitors as suppressors of bone destruction in inflammatory diseases

Objectives Despite progress in developing many new anti‐inflammatory treatments in the last decade, there has been little progress in finding treatments for bone loss associated with inflammatory diseases, such as rheumatoid arthritis and periodontitis. For instance, treatment of rheumatic diseases with anti‐tumour necrosis factor‐alpha agents has been largely successful in reducing inflammation, but there have been varying reports regarding its effectiveness at inhibiting bone loss. In addition, there is often a delay in finding the appropriate anti‐inflammatory therapy for individual patients, and some therapies, such as disease modifying drugs, take time to have an effect. In order to protect the bone, adjunct therapies targeting bone resorption are being developed. This review focuses on new treatments based on using histone deacetylase inhibitors (HDACi) to suppress bone loss in these chronic inflammatory diseases. Key findings A number of selected HDACi have been shown to suppress bone resorption by osteoclasts in vitro and in animal models of chronic inflammatory diseases. Recent reports indicate that these small molecules, which can be administered orally, could protect the bone and might be used in combination with current anti‐inflammatory treatments. Summary HDACi do have potential to suppress bone destruction in chronic inflammatory diseases including periodontitis and rheumatoid arthritis.     

Tracking anti‐fibrotic pathways of nilotinib and imatinib in experimentally induced liver fibrosis: An insight

The tyrosine kinase inhibitors imatinib and nilotinib have been suggested to have promising antifibrotic activity in experimental models of liver fibrosis. The aim of the present study was to investigate new pathways underlying this beneficial effect. Hepatic injury was induced in male Wistar rats by intraperitoneal injection of CCl₄ for 12 weeks. During the last 8 weeks of treatment, rats were also injected daily intraperitoneally with 20 mg/kg imatinib or 20, 10 or 5 mg/kg nilotinib. At the end of treatment, effects on fibrosis were assessed by measuring serum fibrotic markers and profibrogenic cytokines, as well as by histopathological examination. Possible anti‐inflammatory effects were estimated by measuring levels of inflammatory cytokines in liver tissue. Liver expression of α‐smooth muscle actin, transforming growth factor (TGF)‐β1 antibodies and platelet‐derived growth factor receptor β (PDGFRβ) was evaluated by immunohistochemical staining techniques. Nilotinib (5 and 10 mg/kg) significantly (P < 0.05) decreased all serum fibrotic markers measured, but 20 mg/kg of either nilotinib or imatinib had limited effects. At all doses tested, nilotinib significantly (P < 0.05) decreased the CCl₄‐induced increases in tissue inflammatory cytokines. Furthermore, 5 and 10 mg/kg nilotinib significantly decreased TGF‐β1 levels and tissue expression of its antibody, as well expression of PDGFRβ. In conclusion, low doses (5 and 10 but not 20 mg/kg) of nilotinib, rather than imatinib, can control hepatic fibrosis by regulating levels of proinflammatory cytokines, primarily interleukin (IL)‐1 and IL‐6. Nilotinib also controls the signalling pathways of profibrogenic cytokines by lowering TGF‐β1 levels and decreasing expression of PDGFRβ.     

Magnolol Attenuates Concanavalin A‐induced Hepatic Fibrosis,Inhibits CD4+ T Helper 17 (Th17) Cell Differentiation and Suppresses Hepatic Stellate Cell Activation: Blockade of Smad3/Smad4 Signalling

Magnolol is a pharmacological biphenolic compound extracted from Chinese herb Magnolia officinalis, which displays anti‐inflammatory and antioxidant effects. This study was aimed at exploring the potential effect of magnolol on immune‐related liver fibrosis. Herein, BALB/c mice were injected with concanavalin A (ConA, 8 mg/kg/week) up to 6 weeks to establish hepatic fibrosis, and magnolol (10, 20, 30 mg/kg/day) was given to these mice orally throughout the whole experiment. We found that magnolol preserved liver function and attenuated liver fibrotic injury in vivo. In response to ConA stimulation, the CD4⁺ T cells preferred to polarizing towards CD4⁺ T helper 17 (Th17) cells in liver. Magnolol was observed to inhibit Th17 cell differentiation in ConA‐treated liver in addition to suppressing interleukin (IL)‐17A generation. Hepatic stellate cells were activated in fibrotic liver as demonstrated by increased alpha smooth muscle actin (α‐SMA) and desmin. More transforming growth factor (TGF)‐β1 and activin A were secreted into the serum. Magnolol suppressed this abnormal HSC activation. Furthermore, the phosphorylation of Smad3 in its linker area (Thr179, Ser 204/208/213) was inhibited by magnolol. In vitro, the recombinant IL‐17A plus TGF‐β1 or activin A induced activation of human LX2 HSCs and promoted their collagen production. Smad3/Smad4 signalling pathway was activated in LX2 cells exposed to the fibrotic stimuli, as illustrated by the up‐regulated phospho‐Smad3 and the enhanced interaction between Smad3 and Smad4. These alterations were suppressed by magnolol. Collectively, our study reveals a novel antifibrotic effect of magnolol on Th17 cell‐mediated fibrosis.     

Synthesis of Novel Substituted Thiourea and Benzimidazole Derivatives Containing a Pyrazolone Ring as Anti‐Inflammatory Agents

Two series of new 1‐(alkyl/aryl)‐3‐{2‐[(5‐oxo‐4,5‐dihydro‐1H‐pyrazol‐3‐yl)amino]phenyl}thioureas 2a – h and 5‐[2‐(substituted amino)‐1H‐benzimidazol‐1‐yl]‐4H‐pyrazol‐3‐ols 3a – i were designed and synthesized as anti‐inflammatory agents. The cyclooxygenase inhibitory activity of the newly synthesized compounds was investigated. All the compounds showed non‐selective inhibition of COX‐1 and COX‐2 enzymes which was consistent with their docking results. Compounds 2c , 2f , 2g , 3b , and 3g that showed the highest COX‐2 inhibitory activity were selected for further in vivo testing as anti‐inflammatory agents using diclofenac as a reference drug. Two of the test compounds ( 2c and 3b ) showed potent anti‐inflammatory activity comparable to that of diclofenac with lower ulcerogenic effect relative to indomethacin. SAR study of the two series as cyclooxygenase inhibitors and anti‐inflammatory agents was also provided.     

Structure–Activity Relationship of Terpenes with Anti‐Inflammatory Profile – A Systematic Review

Inflammation is a complex biological response that in spite of having available treatments, their side effects limit their usefulness. Because of this, natural products have been the subject of incessant studies, among which the class of terpenes stands out. They have been the source of study for the development of anti‐inflammatory drugs, once their chemical diversity is well suited to provide skeleton for future anti‐inflammatory drugs. This systematic review reports the studies present in the literature that evaluate the anti‐inflammatory activity of terpenes suffering any change in their structures, assessing whether these changes also brought changes in their effects. The search terms anti‐inflammatory agents, terpenes, and structure–activity relationship were used to retrieve English language articles in SCOPUS, PUBMED and EMBASE published between January 2002 and August 2013. Twenty‐seven papers were found concerning the structural modification of terpenes with the evaluation of anti‐inflammatory activity. The data reviewed here suggest that modified terpenes are an interesting tool for the development of new anti‐inflammatory drugs.     

Exploring novel pharmacotherapeutic applications and repurposing potential of sodium glucose CoTransporter 2 inhibitors

Sodium glucose cotransporter 2 (SGLT2) inhibitors are a relatively new class of anti‐hyperglycaemic drugs with a distinctive mechanism of action focusing on renal absorption of glucose. Apart from its anti‐hyperglycaemic effects, a multitude of research studies on this class have revealed that these drugs have far more versatile and comprehensive pharmacological effects than previously believed. Approximately 30% of FDA approved drugs are repurposed and used for indications other than those for which they were initially intended. Repurposing already approved drugs leads to significant reduction in pre‐clinical and clinical R&D costs as well as minimizing the burden with respect to obtaining regulatory approval. SGLT2 inhibitors have been found to exhibit cardioprotective, renoprotective, anti‐hyperlipidaemic, anti‐atherosclerotic, anti‐obesity, anti‐neoplastic, hepatoprotective, and renoprotective effects in in vitro, pre‐clinical, and clinical studies. The pleiotropic effects of this class have been attributed to a variety of its pharmacodynamic actions such as natriuresis, haemoconcentration, deactivation of RAAS, ketone body formation, alterations in energy homeostasis, glycosuria, lipolysis, anti‐inflammatory, and anti‐oxidative actions. These favourable observations encourage further research on this multifaceted class in order to effectively explore and harness its full potential and consequently lead to clinical outcomes.     

Quinoxaline and quinoxaline‐1,4‐di‐N‐oxides: An emerging class of antimycobacterials

Tuberculosis (TB) is a highly dreaded, infectious, chronic, airborne disease affecting more than two million people all around the world, with more than eight million cases every calendar year. TB is the second leading infectious cause of death after HIV/AIDS. Over the past few decades, numerous efforts have been undertaken to develop new anti‐TB agents. The current frontline therapy for TB consists of administering three or more different drugs (usually isoniazid, rifampin, pyrazinamide, and ethambutol) over an extended period of time. But these drugs will take 6–12 months to cure TB, along with many side effects; hence, there is an urgent need to explore new anti‐TB agents. Quinoxaline derivatives are a class of compounds that show a spectrum of biological properties and the interest in these compounds is exponentially growing within the field of medicinal chemistry. Quinoxaline‐1,4‐di‐N‐oxide derivatives have shown to improve the biological results and are endowed with anti‐viral, anti‐cancer, anti‐bacterial, and anti‐protozoal activities with application in many other therapeutic areas. Since quinoxaline derivatives are regarded as a new class of effective anti‐TB candidates, their 1,4‐di‐N‐oxide analogues may show promising in vitro and in vivo anti‐TB activities and might be able to prevent the drug resistance to a certain extent. Therefore, the main aim of this review is to focus on important quinoxaline and quinoxaline‐1,4‐di‐N‐oxide analogues that have shown anti‐TB activities, and their structure–activity relationships for designing anti‐TB agents with better efficacies. The present review will be helpful in providing insights for rational designs of more active and less toxic quinoxaline‐based anti‐TB prodrugs.

     

Opposite actions of urotensin II and relaxin‐2 on cellular expression of fibronectin in renal fibrosis: A preliminary experimental study

Our aim was to evaluate the role of urotensin II, urantide (urotensin II receptor antagonist) and relaxin‐2 on the cellular expression of fibronectin as a surrogate marker for renal fibrosis. We employed LLC‐PK1 renal tubular epithelial cells and assessed the influence on the fibrotic process of the above‐mentioned substances by using anti‐fibronectin antibodies in western blot analysis. The addition of urotensin II increased fibronectin expression. Urantide reduced the positivity for fibronectin caused by urotensin II (P<.05). The anti‐fibrotic action was more evident for relaxin‐2 (P<.01). Also in the model of TGF‐β1‐induced fibrosis, urantide and, to a greater extent, relaxin‐2 were able to significantly lessen fibronectin expression (respectively, P<.05 and P<.01). In conclusion, relaxin‐2 may reduce urotensin II‐induced renal fibrosis.     

A focus on riociguat in the treatment of pulmonary arterial hypertension

Current treatment of pulmonary arterial hypertension (PAH) targets three signalling pathways: the nitric oxide (NO) pathway, the endothelin pathway and the prostacyclin pathway. Riociguat is a soluble guanylate cyclase stimulator, acting via the NO pathway in a new way: unlike other common drugs targeting this pathway (eg tadalafil and sildenafil), riociguat acts independently of endogenous NO. This MiniReview focuses on PAH treatment with riociguat and on its advantages and disadvantages compared with other drugs targeting the NO pathway. In the PATENT‐1 trial (NCT00810693), riociguat improved significantly the 6‐minute walking distance in patients suffering from PAH, with a mean difference (MD) of 36 m compared with a placebo group. The results are comparable to those found for its competitors tadalafil (MD of 33 m) and sildenafil (MD of 50 m) in the PHIRST‐1 trial (NCT00125918) and the SUPER‐1 trial (NCT00644605). No obvious advantages were found regarding pharmacokinetic features and adverse events. In the RESPITE study (NCT02007629), patients with PAH with insufficient response to treatment with tadalafil or sildenafil were switched to riociguat. These results indicate that riociguat might be superior regarding efficacy to PDE‐5 inhibitors in a patient group, where endogenous NO production might be insufficient. This finding was further examined in the REPLACE study (NCT02891850). Moreover, riociguat has shown promising anti‐proliferative, anti‐inflammatory and anti‐fibrotic effects in animal models. Further investigations are needed to determine whether this applies also to human beings. Taken together, riociguat induces vasodilation of the pulmonary arteries and leads to an improvement in the ability to carry out physical activity.     

Cardiovascular effects of sitagliptin – An anti‐diabetes medicine

Dipeptidyl‐peptidase‐4 (DPP‐4) inhibitors, as the most recent available anti‐diabetic agents, were generally used in clinical treatment of type 2 diabetes (T2DM). In addition to anti‐diabetic effects, the five most widely used DPP‐4 inhibitors (sitagliptin, vildagliptin, saxagliptin, linagliptin and alogliptin) also exert cardiovascular protective effects. In recent years, increasing studies suggest that sitagliptin shows pleiotropic impacts towards the cardiovascular system either with or without diabetes. In this review, we summarized the recent reports to provide an update discussion about cardiovascular protective effects of sitagliptin and the corresponding mechanisms. Sitagliptin has positive effects towards ischaemic cardiovascular diseases, atherosclerosis and hypertension. These effects are mainly conducted through DPP‐4 inhibitions. In addition, sitagliptin exerts anti‐inflammation, anti‐oxidative stress, anti‐apoptosis, mediation on lipid accumulation and so on, which also contribute to its cardiovascular effects.     

Telmisartan attenuates peritoneal fibrosis via peroxisome proliferator‐activated receptor‐γ activation in rats

Peritoneal dialysis (PD) is an effective treatment for patients with end‐stage renal diseases, but long‐term continuous PD causes peritoneal fibrosis (PF). This study aims to evaluate the anti‐fibrotic effect of telmisartan on a rat model of PF and to investigate the underlying mechanisms. Five‐sixths kidney nephrectomy and PD were used to establish the PF rat model. Glucose (2.5%) was used to establish an in vitro model in rat peritoneal mesothelial cells (PMC). Haematoxylin–eosin staining was used to examine the structural alterations. Masson's trichrome staining was used to observe the tissue fibrosis in peritoneal membrane of rats. Real‐time polymerase chain reaction was used to measure messenger RNA expressions of profibrotic factors. Western blotting was used to determine protein expressions of profibrotic factors, peroxisome proliferator‐activated receptor‐γ, and mitogen‐activated protein kinases (MAPK). Results demonstrated that administration of telmisartan dose‐dependently attenuated the thickening of the peritoneal membrane and the fibrosis induced by long‐term PD fluid exposure in rats. In addition, telmisartan treatment inhibited the upregulation of profibrotic factors induced by PD in the peritoneum of rats and by high‐concentration glucose in PMC. Telmisartan was also effective in inhibiting PD and high‐concentration, glucose‐induced phosphorylation of MAPK in the peritoneum and PMC. Furthermore, peroxisome proliferator‐activated receptor‐γ (PPARγ) inhibitor GW9662 blocked these protective effects of telmisartan in PMC. The results suggest that telmisartan is effective in attenuating PD‐induced PF, and this effect may be associated with the inhibition of profibrotic factor expression and MAPK phosphorylation via PPARγ activation.     

Systematic review: steroid withdrawal in anti‐TNF‐treated patients with inflammatory bowel disease

Aliment Pharmacol Ther 2010; 32: 313–323

Summary

Background The increasing awareness of increased risk for opportunistic infections when combining several immunosuppressant drugs led to new treatment goals for inflammatory bowel disease including limited use of steroids. Aim To conduct a systematic review to establish figures for steroid withdrawal in anti‐TNF treated inflammatory bowel disease‐patients. Methods Medline was searched using the search‐terms Ulcerative Colitis (UC) [Mesh], Crohn Disease (CD) [Mesh], IBD [Mesh], crohn, colitis, IBD and steroid sparing, all combined with infliximab and adalimumab. We selected English‐language publications that addressed the effect of anti‐TNF on steroid withdrawal. Studies had to assess patients with luminal CD or UC. Numbers of patients who were able to withdraw steroids were calculated. Results Six studies could be included; five reporting on infliximab and one on adalimumab. Studies were heterogeneously designed. Overall, in the adult population, up to 38% of the patients were able to withdraw corticosteroids during infliximab therapy. In the paediatric population, up to 75% of the patients were able to withdraw corticosteroids during infliximab therapy. Conclusions Although a consensus on the definition of steroid‐sparing is lacking, approximately two‐thirds of the inflammatory bowel disease‐patients are unable to withdraw corticosteroid treatment during anti‐TNF therapy.     

Mitogen‐Activated Protein Kinase Phosphatase 1 as an Inflammatory Factor and Drug Target

Mitogen‐activated protein kinases (MAPKs) are signaling proteins that are activated through phosphorylation, and they regulate many physiological and pathophysiological processes in cells. Mitogen‐activated protein kinase phosphatase 1 (MKP‐1) is an inducible nuclear phosphatase that dephosphorylates MAPKs, and thus, it is a negative feedback regulator of MAPK activity. MKP‐1 has been found as a key endogenous suppressor of innate immune responses, as well as a regulator of the onset and course of adaptive immune responses. Altered MKP‐1 signaling is implicated in chronic inflammatory diseases in man. Interestingly, MKP‐1 expression and protein function have been found to be regulated by certain anti‐inflammatory drugs, namely by glucocorticoids, antirheumatic gold compounds and PDE4 inhibitors, and MKP‐1 has been shown to mediate many of their anti‐inflammatory effects. In this Mini Review, we summarize the effect of MKP‐1 in the regulation of innate and adaptive immune responses and its role as a potential anti‐inflammatory drug target and review recent findings concerning the role of MKP‐1 in certain anti‐inflammatory drug effects.     

1‐[(2,3‐Dihydro‐1‐benzofuran‐2‐yl) methyl]piperazines as novel anti‐inflammatory compounds: Synthesis and evaluation on H3R/H4R

The histamine receptors (HRs) are members of G‐protein‐coupled receptor superfamily and traditional targets of huge therapeutic interests. Recently, H₃R and H₄R have been explored as targets for drug discovery, including in the search for dual‐acting H₃R/H₄R ligands. The H₄R, the most recent histamine receptor, is a promising target for novel anti‐inflammatory agents in several conditions such as asthma and other chronic inflammatory diseases. Due to similarity with previously reported ligands of HRs, a set of 1‐[(2,3‐dihydro‐1‐benzofuran‐2‐yl)methyl]piperazines were synthesized and evaluated in competitive binding assays as H₃R/H₄R ligands herein. The results showed the compounds presented affinity (K_i) for H₃R/H₄R in micromolar range, and they are more selective to H₃R. All the compounds showed no important cytotoxicity to mammalian cells. The phenyl‐substituted compound LINS01005 has shown the higher affinity of the set for H₄R, but no considerable selectivity toward this receptor over H₃R. LINS01005 showed interesting anti‐inflammatory activity in murine asthma model, reducing the eosinophil counts in bronchoalveolar lavage fluid, as well as the COX‐2 expression. The presented compounds are valuable prototypes for further improvements to achieve better anti‐inflammatory agents.     

Targeting the Sphingosine Kinase/Sphingosine 1‐Phosphate Pathway to Treat Chronic Inflammatory Kidney Diseases

Chronic kidney diseases including glomerulonephritis are often accompanied by acute or chronic inflammation that leads to an increase in extracellular matrix (ECM) production and subsequent glomerulosclerosis. Glomerulonephritis is one of the leading causes for end‐stage renal failure with high morbidity and mortality, and there are still only a limited number of drugs for treatment available. In this MiniReview, we discuss the possibility of targeting sphingolipids, specifically the sphingosine kinase 1 (SphK1) and sphingosine 1‐phosphate (S1P) pathway, as new therapeutic strategy for the treatment of glomerulonephritis, as this pathway was demonstrated to be dysregulated under disease conditions. Sphingosine 1‐phosphate is a multifunctional signalling molecule, which was shown to influence several hallmarks of glomerulonephritis including mesangial cell proliferation, renal inflammation and fibrosis. Most importantly, the site of action of S1P determines the final effect on disease progression. Concerning renal fibrosis, extracellular S1P acts pro‐fibrotic via activation of cell surface S1P receptors, whereas intracellular S1P was shown to attenuate the fibrotic response. Interference with S1P signalling by treatment with FTY720, an S1P receptor modulator, resulted in beneficial effects in various animal models of chronic kidney diseases. Also, sonepcizumab, a monoclonal anti‐S1P antibody that neutralizes extracellular S1P, and a S1P‐degrading recombinant S1P lyase are promising new strategies for the treatment of glomerulonephritis. In summary, especially due to the bifunctionality of S1P, the SphK1/S1P pathway provides multiple target sites for the treatment of chronic kidney diseases.