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Sant Feliu de Llobregat, Spain

Beier J.,Insaf Respiratory Research Institute | Pujol H.,Astrazeneca | Seoane B.,Astrazeneca | Jimenez E.,Astrazeneca | And 4 more authors.
BMC Pulmonary Medicine | Year: 2016

Background: Abediterol is a novel, once-daily long-acting β2-agonist in development for the treatment of chronic obstructive pulmonary disease (COPD) and asthma in combination with an anti-inflammatory agent. This Phase IIa, randomised, double-blind, crossover study investigated the bronchodilation, safety, tolerability and pharmacokinetics of abediterol in patients with moderate to severe COPD. Methods: Seventy patients (aged ≥40years, Global initiative for chronic Obstructive Lung Disease Stage II/III) were randomised (1:1:1:1:1:1) to single doses of abediterol 0.625, 2.5, 5 or 10μg, indacaterol 150μg or placebo. Spirometry was performed up to 36h post-dose. Pharmacokinetics were assessed in a subset of patients (N=20). Safety and tolerability were evaluated throughout the study. Results: Abediterol (all doses) significantly improved change from baseline in trough forced expiratory volume in 1s (FEV1) compared with placebo (0.102, 0.203, 0.233 and 0.259L for abediterol 0.625, 2.5, 5 and 10μg, respectively; all p<0.0001; primary endpoint). Abediterol 2.5, 5 and 10μg significantly improved trough FEV1 compared with indacaterol 150μg (0.092, 0.122 and 0.148L, respectively; all p<0.0001). Improvements in bronchodilation were maintained at all time points post-dose versus placebo (all abediterol doses) and from 15 or 30min post-dose versus indacaterol 150μg with abediterol 2.5, 5 and 10μg (all p<0.05). Abediterol had low systemic exposure; incidence of treatment-emergent adverse events was similar between treatment groups. Conclusions: All doses of abediterol (0.625-10μg) provided clinically and statistically significant, dose-dependent improvements in bronchodilation versus placebo, and abediterol 2.5, 5 and 10μg gave significant improvements versus indacaterol. All doses of abediterol were safe and well tolerated in patients with COPD. Trial registration: Clinicaltrials.gov NCT01425814. Registered 29 August 2011. © 2016 The Author(s).

Singh D.,University of Manchester | Jones P.W.,St Georges, University of London | Bateman E.D.,University of Cape Town | Korn S.,Mainz University Hospital | And 5 more authors.
BMC Pulmonary Medicine | Year: 2014

Background: Aclidinium/formoterol is a twice-daily (BID) fixed-dose combination (FDC) in development for chronic obstructive pulmonary disease (COPD). The efficacy and safety of aclidinium/formoterol versus monotherapy and placebo in patients with COPD was assessed. Methods: In this 24-week double-blind, parallel-group, active- and placebo-controlled, multicentre Phase III study, patients (≥40 years, post-bronchodilator forced expiratory volume in 1 second [FEV1]/forced vital capacity <70% and FEV1 ≥30% but <80% predicted normal) were randomised 2:2:2:2:1 to aclidinium/formoterol 400/12 μg (n = 385) or 400/6 μg (n = 381), aclidinium 400 μg (n = 385), formoterol 12 μg (n = 384) or placebo (n = 194) BID via Genuair®/Pressair®a. Results: At Week 24, aclidinium/formoterol 400/12 μg and 400/6 μg lead to significant improvements from baseline in 1-hour post-dose FEV1 versus aclidinium (125 mL [95% CI: 90, 160; p < 0 · 001] and 69 mL [95% CI: 34, 105; p < 0.001], respectively) and trough FEV1 versus formoterol (85 mL [95% CI: 51, 119; p < 0.001] and 53 mL [95% CI: 19, 87; p < 0.01], respectively; co-primary endpoints). Additionally, aclidinium/formoterol 400/12 μg and 400/6 μg provided significant improvements in Transition Dyspnoea Index (TDI) focal score versus placebo (1.29 units [95% CI: 0.73, 1.86; p < 0.001] and 1.16 units [95% CI: 0.59, 1.73; p < 0.001], respectively; secondary endpoint). All treatments were well tolerated, with safety profiles of the FDCs similar to those of placebo and monotherapy. Conclusions: Both aclidinium/formoterol BID doses significantly improved bronchodilation versus monotherapy, and dyspnoea versus placebo, with no increase in safety risk. Aclidinium/formoterol may be an effective treatment for patients with COPD. © 2014 Singh et al.

Loza M.I.,University of Santiago de Compostela | Cadavid M.I.,University of Santiago de Compostela | Diaz J.L.,Almirall Randnter | Gavald A.,Almirall Randnter
Bioorganic and Medicinal Chemistry | Year: 2010

A series of pyrazolo[1′,5′:1,6]pyrimido[4,5-d]pyridazin-4(3H)- ones was synthesized and tested in radioligand binding assays to determine their affinities for the human adenosine A1, A2A, A 2B and A3 receptors. Results indicated that this scaffold is appropriate for adenosine receptor subtype A1 ligands and that the best arranged groups around this scaffold are 3- and 4-pyridinyl at position 1, benzyl at position 3, hydrogen at position 6 and 3-thienyl or phenyl at position 9. The most interesting compounds showed Ki for A1 in the nanomolar range and an appreciable selectivity for other receptor subtypes. © 2010 Elsevier Ltd. All rights reserved.

Andres M.,Almirall Randnter | Bravo M.,Almirall Randnter | Buil M.A.,Almirall Randnter | Calbet M.,Almirall Randnter | And 8 more authors.
European Journal of Medicinal Chemistry | Year: 2014

In this manuscript, the synthesis and biological activity of a series of pyrazole acetic acid derivatives as CRTh2 antagonists is presented. Biological evaluation in vitro revealed that the pyrazole core showed in several cases a different structure-activity relationship (SAR) to that of related indole acetic acid. A potent series of ortho-sulfonyl benzyl substituents was found, from which compounds 27 and 63 were advanced to in vivo profiling. © 2013 Elsevier Masson SAS. All rights reserved.

Prat M.,Almirall Randnter | Buil M.A.,Almirall Randnter | Fernandez M.D.,Thomson Reuters | Tort L.,Almirall Randnter | And 13 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2015

Novel quaternary ammonium derivatives of (3R)-quinuclidinyl amides have been identified as potent M3 muscarinic antagonists with a long duration of action in an in vivo model of bronchoconstriction. The synthesis, structure-activity relationships and biological evaluation of this series of compounds are reported. © 2015 Elsevier Ltd.All rights reserved.

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