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N-Protected oxindole derivatives of unprecedented malleability bearing ester moieties at C-3 have been shown to participate in enantioselective phase-transfer-catalysed alkylations promoted by ad-hoc designed quaternary ammonium salts derived from quinine bearing hydrogen-bond donating substituents. For the first time in such phase-transfer-catalysed enolate alkylations, the reactions were carried out under base-free conditions. It was found that urea-based catalysts outperformed squaramide derivatives, and that the installation of a chlorine atom adjacent to the catalyst’s quinoline moiety aided in avoiding selectivity-reducing complications related to the production of HBr in these processes. The influence of steric and electronic factors from both the perspective of the nucleophile and electrophile were investigated and levels of enantiocontrol up to 90% ee obtained. The synthetic utility of the methodology was demonstrated via the concise enantioselective synthesis of a potent CRTH2 receptor antagonist.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a type 2 inflammatory disease of the upper airways. AZD1981 is a selective antagonist of chemoattractant receptor‐homologous molecule expressed on T helper type 2 and other type 2 cells, including innate lymphoid cells type 2, eosinophils, and basophils. Objective: To evaluate the efficacy of AZD1981 in reducing nasal polyp size when added to intranasal corticosteroids in adult patients with CRSwNP. Methods: Eighty‐one subjects (18–70 years of age) with CRSwNP were recruited and screened for trial eligibility from allergy and otolaryngology clinics from a single tertiary care site between June 2016 and August 2019. Eligible patients were randomized in a double‐blind fashion to receive either AZD1981 (n = 22) or placebo (n = 21) orally three times a day for 12 weeks, added to intranasal corticosteroids. The primary endpoint was a change in nasal polyp score (NPS) at 12 weeks. Secondary endpoints included improvement in sinus computed tomography using Lund Mackay scoring, symptoms using visual analog scale, quality of life using Sino Nasal Outcome Test‐22, and the Brief Smell Identification Test. Results: Forty‐three patients met the inclusion criteria and were enrolled. At 12 weeks, there was no difference in NPS change in the AZD1981 arm (mean 0, standard error 0.34, n = 15) compared with placebo (mean 0.20, standard error 0.36, n = 17); mean difference −0.20 (95% confidence interval: −1.21, 0.81; p =.69). No significant differences were observed for Lund Mackay score, symptoms, quality of life, or smell test. AZD1981 was well tolerated except for one case of hypersensitivity reaction. Conclusion: In patients with CRSwNP, the addition of AZD1981 to intranasal corticosteroids did not change nasal polyp size, radiographic scores, symptoms, or disease‐specific quality of life. [ABSTRACT FROM AUTHOR]

Introduction: The chemoattractant receptor expressed on T-helper (Th) type 2 cells (CRTH2) antagonist OC 000459 showed the potential in improving pulmonary function of asthma patients. Aim: We conducted a systematic review and meta-analysis to explore the impact of CRTH2 antagonist OC 000459 on pulmonary function for asthma. Material and methods: PubMed, Embase, Web of science, EBSCO, and Cochrane library databases were systematically searched. This meta-analysis included randomized controlled trials (RCTs) assessing the effect of CRTH2 antagonist OC 000459 on pulmonary function for asthma. Two investigators independently searched articles, extracted data, and assessed the quality of included studies. Results: Four RCTs were included in the meta-analysis. Overall, compared with the control intervention for asthma patients, CRTH2 antagonist OC 000459 could significantly improve FEV1 (SMD = 0.22; 95% CI: 0.02-0.42; p = 0.03), peak expiratory flow (SMD = 0.22; 95% CI: 0.01-0.42; p = 0.04) and reduce the respiratory tract infection (RR = 0.47; 95% CI: 0.26-0.85; p = 0.01), but revealed no remarkable effect on predicted FEV1 (SMD = 0.14; 95% CI: -0.18 to 0.45; p = 0.39), or treatment-related adverse events (RR = 0.84; 95% CI: 0.52-1.36; p = 0.48). Conclusions: CRTH2 antagonist OC 000459 might be effective and safe to improve pulmonary function in asthma patients. [ABSTRACT FROM AUTHOR]

Abstract Background Chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) antagonists are novel agents for asthma but with controversial efficacies in clinical trials. Therefore, we conducted a meta-analysis to determine the roles of CRTH2 antagonists in asthma. Methods We searched in major databases for RCTs comparing CRTH2 antagonists with placebo in asthma. Fixed- or random-effects model was performed to calculate mean differences (MD), risk ratio (RR) or risk difference (RD) and 95% confidence interval (CI). Results A total of 14 trails with 4671 participants were included in our final analysis. Instead of add-on treatment of CRTH2 antagonists to corticosteroids, CRTH2 antagonist monotherapy significantly improved pre-bronchodilator FEV1 (MD = 0.09, 95% CI 0.04 to 0.15, P = 0.0005), FEV1% predicted (MD = 3.65, 95% CI 1.15 to 6.14, P = 0.004), and AQLQ (MD = 0.25, 95% CI 0.09 to 0.41, P = 0.002), and reduced asthma exacerbations (RR = 0.45, 95% CI 0.23 to 0.85, P = 0.01). Rescue use of SABA was significantly decreased in both CRTH2 antagonist monotherapy (MD = − 0.04, 95% CI -0.05 to − 0.03, P

Eric D Bateman,1 Christopher O’Brien,2 Paul Rugman,2 Sally Luke,2 Stefan Ivanov,2 Mohib Uddin2,3 1Department of Medicine, University of Cape Town, Cape Town, 7700, South Africa; 2Research and Development, 3Respiratory, Inflammation, and Autoimmunity, IMED Biotech Unit, AstraZeneca, Gothenburg, SE-431 83, Sweden Objectives: To evaluate the efficacy and safety of AZD1981, a potent, specific antagonist of the CRTh2 receptor, as add-on therapy to inhaled corticosteroids (ICS) and long-acting β2-agonists (LABA), in patients with persistent asthma with an allergic component.Patients and methods: In this placebo-controlled, parallel-group Phase IIb study, patients with persistent atopic asthma on ICS and LABA were randomized to receive 12 weeks of treatment with placebo or AZD1981 (80 mg daily, 200 mg daily, and 10 mg, 40 mg, 100 mg, or 400 mg twice daily [BID]). The primary end point was the mean change from baseline in predose, prebronchodilator forced expiratory volume in 1 second (FEV1) averaged over weeks 2, 4, 8, and 12 in the AZD1981-treatment group vs the placebo group. Secondary end points included other measures of lung function, symptoms, and asthma control, as well as standard measures of safety.Results: In total, 1,140 patients (99.7%) received study treatment. There were improvements in the primary end point across all treatment groups over 12 weeks of treatment. However, the improvement for the highest AZD1981 dose (400 mg BID) vs placebo was not statistically significant (0.02 L, P=0.58), preventing interpretation of statistical testing for the lower doses. AZD1981 was well tolerated, and the incidence of adverse events was comparable across placebo and treatment groups.Conclusion: In patients with allergic asthma receiving ICS and LABA therapy, the addition of AZD1981 at doses up to 400 mg BID failed to produce a clinically relevant improvement in lung function or any other measured end point, but appeared to have an acceptable safety profile. This clinical study is registered with ClinicalTrials.gov (NCT01197794). Keywords: allergic asthma, AZD1981, CRTh2 antagonist, efficacy, safety, eosinophils

Acute lung injury (ALI) and acute respiratory distress syndrome are life-threatening conditions that still have no definite pharmacotherapy. Hence, we investigate the potential effectiveness and underlying mechanism of CT-133, a newly developed selective antagonist of prostaglandin D2 receptor 2 (DP2) or of chemoattractant receptor homologous molecule expressed on Th2 cells (CRTH2), against lipopolysaccharide (LPS)-induced ALI. CT-133 (10 or 30 mg/kg) or dexamethasone (1 mg/kg, positive control) were intragastrically administered 1 h before and 12 h after intratracheal LPS instillation, and primary neutrophils and macrophages and RAW264.7 macrophages were used to investigate the role of CT-133 in regulation of their functions. LPS induced a significant secretion of PGD 2 from primary macrophages, however, CT-133 dose-dependently and markedly decreased the infiltration of neutrophils and macrophages into lungs, reduced the IL-1β, TNF-α, IL-6, and KC levels in broncho-alveolar lavage (BAL) fluids, decreased the wet weight and myeloperoxidase activity of lungs, reduced Evans blue and albumin exudation into lungs, and improved the lung histopathological changes and hypoxemia. Moreover, CT-133 significantly suppressed the primary neutrophil migration toward the PGD 2 and robustly inhibited the mRNA and protein expression of IL-1β, TNF-α, IL-6, and KC in primary and RAW264.7 macrophages in response to either LPS- or PGD 2 stimulation. Finally, CT-133 significantly blocked the LPS-induced P65 activation in both RAW264.7 macrophages and mouse lungs. Thus, This is the first report that a CRTH2 antagonist, CT-133, is capable of significantly alleviating LPS-induced lung injury by probably down-regulating the NF-κB signalling. [ABSTRACT FROM AUTHOR]

Abstract Aims Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), characterized by overwhelming lung inflammation, are associated with high mortality. Cigarette smoke (CS) is one of the major causes of ALI/ARDS. Since high expression of prostaglandin (PG) D 2 has been observed in CS-induced lung injury. Currently, no effective pharmacological therapies are available to treat ALI, and supportive therapies remain the mainstay of treatment. Therefore, we investigated the protective effect of CT‑133, a newly discovered selective CRTH2 antagonist, on CS-induced ALI in vivo and in vitro. Main methods CT‑133 (10 and 30 mg/kg), dexamethasone (1 mg/kg) and normal saline were intratracheally administrated 1 hr prior to whole-body CS-exposure for seven consecutive days to study the key characteristics of ALI. Subsequently, CSE (4%)- and PGD 2 -stimulated RAW 264.7 macrophages were used to evaluate the protective effect of CT‑133. Key findings CT‑133 remarkably attenuated infiltration of inflammatory cells, neutrophils, and macrophages in the BALF, albumin contents, expression of IL‑1β, IL‑6, TNF‑α and KC, lung myeloperoxidase (MPO) activity and lung histopathological alterations caused by CS exposure in mice. Moreover, CT‑133 not only reversed the uncontrolled secretion of IL‑1β, IL-6, TNF‑α and KC from CSE- and PGD 2 -stimulated RAW 264.7 macrophages but also augmented IL-10 production in both in vivo and in vitro studies. Additionally, CT‑133 alleviated in vitro neutrophil migration chemoattracted by PGD 2. Significance Our results provide the first evidence that targeting CRTH2 could be a new potential therapeutic option to treat CS-induced ALI. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

BI 1021958, a novel antagonist of the chemoattractant-receptor-homologous molecule (CRTH2), targets airway inflammation in asthma by inhibiting prostaglandin binding to CRTH2 receptors. Two phase 1 studies assessed BI 1021958 safety/tolerability and pharmacokinetics (PK)/pharmacodynamics (PD) following single doses in healthy men and multiple doses in men/women with well-controlled asthma. Studies 1 had 2 parts: a placebo-controlled, fixed-sequence, single-blind, single-rising-dose part (n = 56) and a randomized, 2-way crossover, open-label, repeated-dose part studying the food effect on PK/PD (n = 12). Study 2 was a placebo-controlled, single-center, double-blind multiple-rising-dose study (n = 84). Primary end points were safety/tolerability and PK/PD (both studies); secondary end points were eosinophil shape change (ESC; study 1) and dose proportionality/linearity following first dose and at steady state (study 2). BI 1021958 was adequately tolerated in both studies; adverse events were infrequent, generally mild to moderate, and occurred similarly in treatment groups. Maximum measured concentration (Cmax) was achieved in ≤2.5 hours in study 1 and ≤2.0 hours in study 2. BI 1021958 exposure increased proportionally with dose. In study 1, following a single 60-mg dose, AUC parameters and Cmax were 20% and 15% lower, respectively, after a high-fat meal compared with the fasted state. After ≥60-mg single doses (study 1) and >40-mg multiple doses (study 2), >95% ESC inhibition was observed for ≥24 hours. PK/PD was similar in healthy subjects and subjects with well-controlled asthma. Data support further investigation of CRTH2 antagonists for the treatment of asthma. [ABSTRACT FROM AUTHOR]

Monocyclic and bicyclic ring systems were investigated as the “core” section of a series of diphenylsulphone-containing acetic acid CRTh2 receptor antagonists. A range of potencies were observed and single-digit nanomolar potencies were obtained in both the monocyclic and bicyclic cores. Residence times for the monocyclic compounds were very short. Some of the bicyclic cores displayed better residence times. A methyl group in the northern part of the core, between the head and tail was a necessary requirement for the beginnings of long residence times. Variations of the tail substitution maximised potencies and residence times. [ABSTRACT FROM AUTHOR]

The prostaglandin D 2 (PGD 2 ) receptor, CRTH2, plays a role in allergic airway inflammation. The efficacy of BI 671800, a CRTH2 antagonist, was assessed in 2 separate trials in patients with asthma, in either the absence or the presence of inhaled corticosteroid (ICS) therapy. In this study, BI 671800 (50, 200 or 400 mg) and fluticasone propionate (220 μg) all given twice daily (bid) were compared with bid placebo in symptomatic controller-naïve adults with asthma (Trial 1), and BI 671800 400 mg bid compared with montelukast 10 mg once daily (qd), and matching placebo bid, in patients with asthma receiving inhaled fluticasone (88 μg bid) (Trial 2). The primary endpoint in both trials was change from baseline in trough forced expiratory volume in 1 s (FEV 1 ) percent predicted. After 6 weeks' treatment, adjusted mean treatment differences (SE) for the primary endpoint compared with placebo in Trial 1 were 3.08% (1.65%), 3.59% (1.60%) and 3.98% (1.64%) for BI 671800 50, 200 and 400 mg bid, respectively, and 8.62% (1.68%) for fluticasone 220 μg bid ( p = 0.0311, p = 0.0126, p = 0.0078 and p < 0.0001, respectively). In Trial 2, adjusted mean FEV 1 (SE) treatment differences compared with placebo were 3.87% (1.49%) for BI 671800 400 mg bid and 2.37% (1.57%) for montelukast ( p = 0.0050 and p = 0.0657, respectively). These findings suggest that BI 671800 is associated with a small improvement in FEV 1 in symptomatic controller-naïve asthma patients, and in patients on ICS. [ABSTRACT FROM AUTHOR]

A knowledge-based design strategy led to the discovery of several new series of potent and orally bioavailable CRTh2 antagonists where a bicyclic heteroaromatic ring serves as the central core. Structure–kinetic relationships (SKR) opened up the possibility of long receptor residence times. [ABSTRACT FROM AUTHOR]

Pyrrolopiperidinone acetic acids (PPAs) were identified as highly potent CRTh2 receptor antagonists. In addition, many of these compounds displayed slow-dissociation kinetics from the receptor. Structure–kinetic relationship (SKR) studies allowed optimisation of the kinetics to give potent analogues with long receptor residence half-lives of up to 23 h. Low permeability was a general feature of this series, however oral bioavailability could be achieved through the use of ester prodrugs. [ABSTRACT FROM AUTHOR]

Background CRTH2 is a G-protein-coupled receptor on T helper2 cells that mediates pro-inflammatory effects of prostaglandin D2 in allergic responses. Objective To investigate the tolerability and pharmacokinetics of setipiprant ( ACT-129968), a selective orally active CRTH2 antagonist, in allergic asthmatics and to assess the protective effects of multiple doses of this drug against allergen-induced airway responses. Methods In this 3-centre, double-blinded, placebo-controlled, cross-over study, 18 allergic asthmatic males were randomized to setipiprant 1000 mg or matching placebo b.i.d. for 5 consecutive days. Study periods were separated by a washout of ≥ 3 weeks. On study day 4, subjects underwent a standardized allergen challenge and airway response was recorded by FEV1 until 10 h post-allergen. Airway responsiveness to methacholine and exhaled nitric oxide (e NO) were measured pre- and post-dosing. The effects of both treatments on the allergen-induced airway responses were compared by a paired Student's t-test. Results Fifteen subjects completed the study per-protocol and were included in the analysis. Overall, setipiprant was well tolerated and no clinically relevant adverse events occurred. Trough plasma concentrations showed a high inter-subject variability. Compared with placebo, setipiprant significantly reduced the allergen-induced late asthmatic response (LAR), inhibiting the area under the response vs. time curve ( AUC(3-10 h)) by on average 25.6% ( P = 0.006) and significantly protected against the allergen-induced airway hyperresponsiveness ( AHR) to methacholine ( P = 0.0029). There was no difference in the early asthmatic response ( EAR) or in allergen-induced changes in e NO between treatments. Conclusion and Clinical Relevance Setipiprant at multiple oral doses was well tolerated and reduced both the allergen-induced LAR and the associated AHR in allergic asthmatics. Our findings confirm that CRTH2 may be a promising target for the treatment of allergic disorders. [ABSTRACT FROM AUTHOR]

Abstract: In this study, we describe the synthesis and structure–activity relationship (SAR) of a series of isoquinoline chemoattractant receptor–homologous molecule expressed on Th2 cells (CRTH2) antagonists. TASP0376377 (15-20), one of the most potent compounds, showed a potent binding affinity (IC50 =19nM) in addition to the excellent functional antagonist activity (IC50 =13nM). Moreover, the efficacy of this compound in a chemotaxis assay (IC50 =23nM) was in good agreement with its potency as a CRTH2 antagonist. In addition, 15-20 exhibited greater selectivity in binding to CRTH2 than to the DP1 prostanoid receptor (IC50 >1μM) or the enzymes COX-1 and COX-2 (IC50 >10μM). [Copyright &y& Elsevier]

Objective: To evaluate the efficacy and tolerability of the selective CRTh2 (DP2) receptor antagonist AZD1981 compared with placebo in patients with moderate to severe COPD. Methods: In this multicentre, randomised, double-blind, parallel-group, phase IIa study (ClinicalTrials.gov identifier: NCT00690482) patients with moderate to severe COPD received either AZD1981 1000 mg twice daily or matching placebo for 4 weeks. Inhaled terbutaline was used as-needed as reliever medication throughout. The co-primary endpoints were change from baseline to end of treatment in pre-bronchodilator forced expiratory volume in 1 s [FEV1] and the Clinical COPD Questionnaire (CCQ). Additional endpoints included other lung function measures, 6-min walk test (6-MWT), COPD symptom score, reliever medication use and tolerability. Results: 118 patients were randomised to treatment (AZD1981 n = 61; placebo = Z57); 83% of patients were male and the mean age was 63 years (range 43-83). There were no significant differences in the mean difference in change from baseline to end of treatment between AZD1981 and placebo for the co-primary endpoints of pre-bronchodilator FEV1 (AZD1981 eplacebo:0.015, 95% CI:0.10 to 0.070; p = 0.72) and CCQ total score (difference: 0.042, 95% CI:0.21 to 0.30; p = 0.75). Similarly, no differences were observed between treatments for the other outcomes of lung function, COPD symptom score, 6-MWT, BODE index, and use of reliever medication. AZD1981 was well tolerated. Conclusion: There was no beneficial clinical effect of AZD1981, at a dose of 1000 mg twice daily for 4 weeks, in patients with moderate to severe COPD. AZD1981 was well tolerated and no safety concerns were identified. [ABSTRACT FROM AUTHOR]

Background Eosinophilic esophagitis ( Eo E) is a chronic, Th2-type inflammatory disease. Chemoattractant receptor-homologous molecule on Th2 cells ( CRTH2) is a prostaglandin D2 ( PGD2) receptor, expressed by Th2 cells and other inflammatory cells, including eosinophils and basophils, that mediates chemotaxis and activation. OC000459 is a selective CRTH2 antagonist and would be expected to suppress eosinophilic tissue inflammation. The purpose of this study was to evaluate the efficacy and safety of an OC000459 monotherapy in adult patients with active, corticosteroid-dependent or corticosteroid-refractory Eo E. Methods In this randomized, double-blind, placebo-controlled trial, 26 adult patients (m/f = 22/4; mean age 41 years, range 22-69 years) with active Eo E, dependent or resistant to corticosteroids, were treated either with 100 mg OC000459 ( n = 14) or placebo ( n = 12) twice daily. Pre- and post-treatment disease activity was assessed clinically, endoscopically, histologically, and via biomarkers. The primary end point was the reduction in esophageal eosinophil infiltration. Results After an 8-week OC000459 treatment, the esophageal eosinophil load decreased significantly, from 114.83 to 73.26 eosinophils per high-power field [(eos/hpf), P = 0.0256], whereas no reduction was observed with placebo (102.80-99.47 eos/hpf, P = 0.870). With OC000459, the physician's global assessment of disease activity improved from 7.13 to 5.18 ( P = 0.035). OC000459 likewise reduced extracellular deposits of eosinophil peroxidase and tenascin C, the effects not seen with placebo. No serious adverse events were observed. Conclusions An 8-week treatment with the CRTH2-antagonist, OC000459, exerts modest, but significant, anti-eosinophil and beneficial clinical effects in adult patients with active, corticosteroid-dependent or corticosteroid-refractory EoE and is well tolerated. [ABSTRACT FROM AUTHOR]

Allergic rhinitis has the greatest prevalence of any respiratory disease and affects about 20% of the population in North America and Europe. There is an increasing need for allergen challenge systems to test anti-allergic drugs under well-controlled conditions. The allergen challenge chamber ( ACC) is a room that enables reproducible challenges with controlled levels of inhalant allergens, temperature and humidity for several hours. ACCs have been used in Europe, North America and Japan to evaluate symptomatic and anti-inflammatory medications for the treatment of allergic rhinitis. This review summarizes the experience with a typical ACC in Germany, the Fraunhofer Challenge Chamber, and describes the stability and reproducibility of the allergen exposure in the chamber. It further provides data for the specificity and reproducibility of clinical read-out parameters, such as nasal symptom scores, nasal flow rates and nasal secretions, as well as of nasal biomarkers obtained in different validation studies. Typical study designs for testing the acute and prophylactic treatment effects of anti-allergic substances are discussed. Regulatory authorities, such as the FDA and EMA, recommend the use of ACCs in drug development to evaluate the optimal dose and onset of action during early clinical development. In combination with natural-exposure Phase III studies, they provide supportive evidence of superiority over placebo as an additional pharmacodynamic assessment tool. In particular, ACC studies may be of additional value in the clinical development of immunotherapy, because the variability of natural allergen exposure hampers the demonstration of efficacy in clinical trials. [ABSTRACT FROM AUTHOR]

Abstract: Synthesis and structure–activity relationship of a novel series of isoquinoline CRTH2 receptor antagonists are described. One of the most potent compounds, TASP0376377 (6m), showed not only potent binding affinity (IC50 =19nM) but also excellent functional antagonist activity (IC50 =13nM). TASP0376377 was tested for its ability of a chemotaxis assay to show the effectiveness (IC50 =23nM), which was in good agreement with the CRTH2 antagonist potency. Furthermore, TASP0376377 showed sufficient selectivity for binding to CRTH2 over the DP1 prostanoid receptor (IC50 >1μM) and COX-1 and COX-2 enzymes (IC50 >10μM). [Copyright &y& Elsevier]

Abstract: In this manuscript we wish to report the discovery of MK-7246 (4), a potent and selective CRTH2 (DP2) antagonist. SAR studies leading to MK-7246 along with two synthetic sequences enabling the preparation of this novel class of CRTH2 antagonist are reported. Finally, the pharmacokinetic and metabolic profile of MK-7246 is disclosed. [Copyright &y& Elsevier]

ABSTRACT It is known that thromboxane A2 (TXA2) contributes to various diseases such as bronchial asthma, ischemic heart disease, cerebrovascular disorders and allergic rhinitis. A number of TXA2 synthase inhibitors and TXA2 receptor (TP receptor) antagonists have been developed to treat these diseases. Ramatroban (BAY u 3405) was developed as a potent TP receptor antagonist with excellent efficacy against allergic rhinitis in many animal models and patients. Recent studies also revealed that ramatroban can block the newly identified PGD2 receptor, chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2). PGD2 induces migration and degranulation of eosinophils through CRTh2 and contributes to late-phase inflammation and cell damage. Accordingly, it was considered that ramatroban suppresses the late-phase inflammation via TP receptor and CRTh2 blockade. In terms of the efficacy on vascular systems, it was revealed that ramatroban can suppress the expression of monocyte chemoattractant protein-1 (MCP-1) and adhesion molecules in endothelial cells and prevent exacerbation of inflammation by blocking these responses. According to our recent studies in hypercholesterolemic rabbits ramatroban prevents macrophage infiltration through MCP-1 downregulation and neointimal formation after balloon injury and attenuates vascular response to acetylcholine. Therefore, ramatroban may be beneficial in the treatment of atherosclerosis. [ABSTRACT FROM AUTHOR]

Selection of acidic or basic reaction conditions, combined with appropriate temperatures, allowed for site selective direct incorporation of deuterium at multiple positions in the 7-azaindole-3-acetic acid CRTh2 receptor antagonist clinical candidate NVP-QAV680. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) antagonists are novel agents for asthma but with controversial efficacies in clinical trials. Therefore, we conducted a meta-analysis to determine the roles of CRTH2 antagonists in asthma.Methods: We searched in major databases for RCTs comparing CRTH2 antagonists with placebo in asthma. Fixed- or random-effects model was performed to calculate mean differences (MD), risk ratio (RR) or risk difference (RD) and 95% confidence interval (CI).Results: A total of 14 trails with 4671 participants were included in our final analysis. Instead of add-on treatment of CRTH2 antagonists to corticosteroids, CRTH2 antagonist monotherapy significantly improved pre-bronchodilator FEV1 (MD = 0.09, 95% CI 0.04 to 0.15, P = 0.0005), FEV1% predicted (MD = 3.65, 95% CI 1.15 to 6.14, P = 0.004), and AQLQ (MD = 0.25, 95% CI 0.09 to 0.41, P = 0.002), and reduced asthma exacerbations (RR = 0.45, 95% CI 0.23 to 0.85, P = 0.01). Rescue use of SABA was significantly decreased in both CRTH2 antagonist monotherapy (MD = - 0.04, 95% CI -0.05 to - 0.03, P < 0.00001) and as add-on to corticosteroids (MD = - 0.78, 95% CI -1.47 to - 0.09, P = 0.03). Adverse events were similar between the intervention and placebo groups.Conclusions: CRTH2 antagonist monotherapy can safely improve lung function and quality of life, and reduce asthma exacerbations and SABA use in asthmatics. [ABSTRACT FROM AUTHOR]