Interleukin-5 Inhibitors Research Articles

CoMFA and CoMSIA Analyses of Novel Chromenone Derivatives as Interleukin 5 Inhibitors

Abstract: Major allergic diseases are caused by an increased accumulation of eosinophils driven by interleukin 5 (IL-5). Chromenone analogues have been demonstrated as a promising scaffold for IL-5 inhibitors to control allergic diseases. Therefore, the molecular interaction of IL-5 inhibitors with biological targets is important for better drug discovery. In this study, we analysed in vitro data using 3D-QSAR (Quantitative Structure-Activity Relationships) modelling to find the IL-5 inhibitory activity and molecular interaction. The results of Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Field Similarity Indices (CoMSIA IB) revealed that the in vitro IL-5 inhibitory activity of these chromenone derivatives exhibited strong correlations with steric and electrostatic factors of the molecules (q2 =0.503, r_ncv^2 = 0.997, and r_bs^2 = 0.989 for CoMFA standard model and q2 =0.623, r_ncv^2 = 0.973, and r_bs^2 = 0.990 for CoMSIA model). 3D-QSAR field contour maps could be generated to identify the important structural features of chromenone analogues relevant to the IL-5 inhibitory activity.

Taking a Breather: Advances in Interleukin 5 Inhibition for Asthma Relief.

Interleukin 5 (IL-5) is a major cytokine responsible for eosinophil proliferation, migration and degranulation. Eosinophils play a considerable role in the manifestation of type 2 asthma, and therefore this makes IL-5 a unique and clinically important target for therapeutic intervention. Due to the critical role that IL-5 plays in all areas of eosinophil activity, it has been identified and targeted by three therapeutics, Mepolizumab, Benralizumab and Reslizumab. This review describes the IL-5 pathway and presents the clinical trial history of the three IL-5 inhibitors, to provide insight into the role of IL-5 in clinical asthma presentation. Additionally, this review aims to foster further investigation into the IL-5 pathway by describing current novel therapeutic discovery strategies with monoclonal antibodies.

Refractory flare-up of severe bronchial asthma controlled with mepolizumab due to Pneumocystis pneumonia: a case report

BackgroundBiologics dramatically improve symptoms of severe asthma; however, various exacerbating factors may induce flare-up. Pneumocystis spp. have not been reported as a cause of asthma exacerbation during biologic use, although patients with severe asthma have high levels of antibodies against Pneumocystis spp.Case presentationAn 87-year-old female with severe asthma that was well-controlled with mepolizumab, who developed a steroid-resistant refractory flare-up. Chest computed tomography showed bilateral ground glass opacities, and results of polymerase chain reaction tests on induced sputum were positive for Pneumocystis DNA. Therefore, a diagnosis of Pneumocystis pneumonia was made. The clinical symptoms improved after treatment with sulfamethoxazole–trimethoprim.ConclusionClinicians should be aware of Pneumocystis pneumonia as a cause of refractory exacerbation of bronchial asthma during use of interleukin-5 inhibitors.

Poor control of asthma symptoms with interleukin-5 inhibitors in four patients with aspirin-exacerbated respiratory disease

Poor control of asthma symptoms with interleukin-5 inhibitors in four patients with aspirin-exacerbated respiratory disease

Discovery of benzimidazole analogs as a novel interleukin-5 inhibitors

A series of novel hydroxyethylaminomethylbenzimidazole analogs 5a-y were synthesized and evaluated for their IL-5 inhibitory activity using pro-B Y16 cell line. Among them, 2-(((4-(cyclohexylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)amino)butan-1-ol (5e, 94.3% inhibition at 30 μM, IC50 = 3.5 μM, cLogP = 4.132) and 3-cyclohexyl-2-(((4-(cyclohexylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)amino) propan-1-ol (5k, 94.7% inhibition at 30 μM, IC50 = 5.0 μM, cLogP = 6.253) showed the most potent inhibitory activity. The essential feature of SAR (Fig. 5) indicated that the chromenone ring can be replaced by a benzimidazole ring to maintain the inhibitory activity. In addition, the hydroxyethylaminomethyl group was suitable for the IL-5 inhibitory activity. Moreover, the hydrophobic substituents on carbon play an important role in the IL-5 inhibitory activity of these analogs. However, N-substituted analogs did not improve inhibitory activity. In addition, MTT assay of 5e and 5k with normal B lymphoblasts revealed that they had no significant effects on cell viability.

Matching-adjusted indirect comparison of benralizumab versus interleukin-5 inhibitors for the treatment of severe asthma: a systematic review.

Benralizumab is an interleukin-5 receptor α-directed cytolytic monoclonal antibody that directly depletes eosinophils. Its relative efficacy versus other IL-5-targeted treatments for patients with severe, uncontrolled asthma is not yet fully characterised.We performed a matching-adjusted indirect comparison (MAIC) of benralizumab versus mepolizumab and reslizumab. Trials were selected through systematic review and evaluation of trial methods. Benralizumab patient-level data were weighted to match treatment-effect-modifying patient characteristics of comparator trials before indirect efficacy comparisons.After matching adjustment, benralizumab and mepolizumab reduced exacerbations versus placebo by 52% and 49%, respectively (rate ratio [RR] 0.94, 95% CI 0.78–1.13; n=1524) and reduced the rate of exacerbations requiring hospitalisation/emergency department visit by 52% and 52%, respectively (RR 1.00, 95% CI 0.57–1.75; n=1524). Benralizumab and mepolizumab similarly improved pre-bronchodilator forced expiratory volume in 1 s at 32 weeks (difference 0.03 L, 95% CI −0.06–0.12; n=1443). Benralizumab and reslizumab patient populations were too dissimilar to generate a sufficient effective sample size to produce a reliable estimate for MAIC.MAIC is a robust way to indirectly compare treatment efficacies from trials with heterogeneous patient populations. When baseline patient characteristics were matched across asthma trials, benralizumab and mepolizumab yielded similar efficacy.

Identification of novel 2-benzyl-1-indanone analogs as interleukin-5 inhibitors

A novel series of 2-benzyl-1-indanone analogs were investigated as IL-5 inhibitory activity. Among the synthesized compounds, 7-(cyclohexylmethoxy)-2-(4-hydroxybenzyl)-2,3-dihydro-1H-inden-1-one (7s, 100.0% inhibition at 30 μM, IC50 = 4.0 μM), and 7-(cyclohexylmethoxy)-2-(3-hydroxybenzyl)-2,3-dihydro-1H-inden-1-one (7t, 95.0% inhibition at 30 μM, IC50 = 6.0 μM) showed the best inhibitory activity against IL-5. The 2-benzyl-1-indanone analogs showed moderate to strong IL-5 inhibitory activity. Especially, hydroxyl (HBD/HBA) substituent at position 3 or 4 on phenyl ring B showed potent IL-5 inhibition. Additionally, the bulky hydrophobic cyclohexylmethoxy group at position 7 of the 1-indanone ring is favorable for the inhibitory activity.

Discovery of novel 3-(hydroxyalkoxy)-2-alkylchromen-4-one analogs as interleukin-5 inhibitors

A series of novel chromen-4-one analogs 9a-d and 10a-u was designed, synthesized and evaluated for their IL-5 inhibitory activity. Most of the chromen-4-one analogs showed strong inhibitory activity in low micro molar potency. Among them, 5-(cyclohexylmethoxy)-3-(3-hydroxypropoxy)-2-isopropyl-4H-chromen-4-one (10t, 90.0% inhibition at 30 μM, IC50 = 5.5 μM, CLogP = 4.76887) and 2-cyclohexyl-5-(cyclohexylmethoxy)-3-(3-hydroxypropoxy)-4H-chromen-4-one (10u, 95.5% inhibition at 30 μM, IC50 = 3.0 μM, CLogP = 5.96187) showed the best inhibition. The structure activity relationship reveals that the hydrophobic cyclohexylmethoxy group at the position 5 of the chromen-4-one ring A is preferable than at position 6 and the dual hydrogen bonding acceptor property on the chromen-4-one ring should be important for the inhibitory activity. In addition, the optimum length of the side chain at position 3 of chromen-4-one ring is critical for the donation of hydrogen to the binding site and the 3-hydroxypropoxy group showed the best activity. Moreover, the conformational restrictor (isopropyl, cyclohexyl group) at position 2 is much more favorable for the formation of effective conformer of side chain with hydrogen bonding donor property of these chromen-4-one analogs.

Eosinophilic Gastroenteritis and Colitis: a Comprehensive Review.

Eosinophilic gastrointestinal disorders, including eosinophilic esophagitis, gastroenteritis, and colitis, refer to a spectrum of clinical diseases that present with variable degrees of infiltration of the gastrointestinal tract by eosinophils in the absence of other known causes of tissue eosinophilia. Clinical symptoms and laboratory findings are usually non-specific and may or may not be accompanied by peripheral blood eosinophilia. The extent of eosinophilic infiltration of the gastrointestinal wall varies from mucosal to transmural and serosal involvement. Diagnosis requires presence of gastrointestinal symptoms, demonstration of gastrointestinal eosinophilia by biopsy, and exclusion of other known causes of tissue eosinophilia. Many studies have pointed toward the eosinophil as the major offender; however, the exact functional role of the eosinophil in the pathogenesis of eosinophilic gastrointestinal disorders remains unclear. The roles of T-helper-2 cytokines and other mediators, such as eotaxin-1 and interleukin-5, have gained significant importance in the pathobiology of eosinophilic gastrointestinal disorders. Current understanding of treatment is based on case reports and a few case series, as there is a lack of large prospective studies. Steroids are currently the mainstay of therapy, but the roles of other drugs such as leukotriene inhibitors, mast cell stabilizers, interleukin-5 inhibitors, and anti-immunoglobulin E, along with other targets in the immune pathway, are currently being explored.

Exploration of benzamidochromenone derivatives with conformational restrictor as interleukin-5 inhibitors

Novel amidochromen-4-one analogs 8a–k and 9a–f were prepared and studied for their IL-5 inhibitory activity. Among the synthesized compounds, (6-benzamido-2-cyclohexyl-4-oxo-4H-chromen-3-yl)methyl acetate (8a, 95% inhibition at 30μM, IC50=6.1μM) exhibited potent IL-5 inhibitory activity. The conformational restrictor at position 2 like bulky cyclohexyl group is favorable for the formation of effective conformer of side chain small ester like acetoxymethyl at position 3 of these chromenone analogs 8. In addition the hydrophobic planarity of benzamido group at position 6 should be important for the potent IL-5 inhibitory activity. Since replacing acetoxymethyl moiety with hydroxymethyl group at position 3 of chromenone decreases the activity, which indicates that the location of hydrogen bonding group should be near 4 atom distances away from chromenone ring is more optimum for the activity. Therefore, these benzamidochromen-4-one analogs 8 are novel scaffold for finding potent interleukin-5 inhibitors.

Design and synthesis of novel chromenone derivatives as interleukin-5 inhibitors

A novel series of chromenone analogs were synthesized and evaluated for their inhibitory activity against interleukin-5. Among them 5-(cyclohexylmethoxy)-3-[3-hydroxy-3-(4-hydroxyphenyl)propyl]-4H-chromen-4-one (9b, 94% inhibition at 30μM, IC50=4.0μM) and 5-(cyclohexylmethoxy)-3-[3-hydroxy-3-(4-methoxyphenyl)propyl]-4H-chromen-4-one (9c, 94% inhibition at 30μM, IC50=6.5μM) showed the most potent activity. According to the SAR studies introduction of propanone unit in between chromenone and ring B as in 5-(cyclohexylmethoxy)-3-[3-(4-phenyl)-3-oxopropyl]-4H-chromen-4-ones (8) moderately increased the activity. However, the reduction of these propanones 8 to propanols 9 remarkably enhanced the activity. A small substituent at position 4 of ring B in 9, especially with hydrogen bonding capability, provides favorable contribution. Disappearance of IL-5 inhibitory activity upon saturation of chroman-4-one of 9 to chroman-4-ones 10 proves the critical importance of planar chromen-4-one unit of this scaffold in the IL-5 inhibition.

Identification of novel chromenone derivatives as interleukin-5 inhibitors

A series of (E)-5-alkoxy-3-(3-phenyl-3-oxoprop-1-enyl)-4H-chromen-4-ones (4) and (E)-5-alkoxy-3-(3-hydroxy-3-phenylprop-1-enyl)-4H-chromen-4-ones (5) were synthesized and evaluated for their IL-5 inhibitory activity. Propenone analogs 4 possess some of the structurally important characteristics of isoflavone 2 and chalcone 3 previously known as potent IL-5 inhibitor. However, the inhibitory activity of 4 was weak and therefore this structural hybridization appears to be ineffective for the design of IL-5 inhibitor. Meanwhile the potent activity profile of compounds 5 was discovered. This enhanced activity of 5 compared to 4 could be due to the effective location of hydroxyl group of allylic alcohol moiety of 5 in the 3D structure. The electron withdrawing substituents at position 4 of phenyl ring of 5 enhances the activity possibly due to an increase in the strength of hydrogen bonding property of hydroxyl group of allylic alcohol moiety.

Novel interleukin-5 inhibitors based on hydroxyethylaminomethyl-4H-chromen-4-one scaffold

Hydroxyethylaminomethyl-4H-chromenones were previously discovered as fairly strong IL-5 inhibitor. For determination of detail structure activity relationship, N-substituted hydroxyethylaminomethylchromenones 4a–n were prepared and evaluated for their IL-5 inhibitory activity. Shifting the hydrophobic group to nitrogen from 1-position of hydroxyethylamino moiety of hydroxyethylaminomethyl-4H-chromenones enhances the activity. The increment in bulkiness or hydrophobicity of alkyl side chain at amino group increases the activity. The same level of activity of 5-(cyclohexylmethoxy)-3-(N-benzyl-2-hydroxyethylaminomethyl)-4H-chromenone analogs regardless of hydrophobic or hydrophilic substituents at 4th position of phenyl ring might infer the existence of tunnel structure in the putative receptor for accepting these side chains.

Treatment of Eosinophilic Esophagitis in Children.

Eosinophilic esophagitis (EE) is an important esophageal disorder with distinct clinicopathologic features, and the condition is associated with a high prevalence of food allergies and atopy. In the past decade, we have improved our ability to recognize the phenotype of EE, but our ability to treat EE effectively remains limited despite several reports of successful treatment using elemental or elimination diets, and systemic and topical corticosteroids. The limitations for developing effective treatment regimens are due to some still unresolved and ambiguous aspects of the pathogenesis of EE. Neither the predisposing factors for developing EE in a subset of patients with atopy, nor the variable responsiveness to control measures for allergens are fully understood. There also remain questions about the precise role of gastroesophageal reflux, and the natural history of the disorder, contingent on which is the optimal treatment of EE. In devising treatment for a patient with EE, all attempts should be made to identify and control food and other allergies. In patients who have no diagnosed allergies or who are unresponsive to allergy treatment, topical steroids are a safe and effective treatment option. Systemic steroids should be reserved for those patients who are refractory to topical steroids. Beyond the initial phase of induction treatment, it is crucial to develop effective and safe maintenance treatment regimens based on ongoing allergen control and mast cell inhibitors. There are limited but encouraging data to support further exploration of the role of leukotriene and interleukin-5 inhibitors as safe, effective, and steroid-sparing treatment options.