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Aparici M.,Almirall R and nter | Gomez-Angelats M.,Almirall R and nter | Vilella D.,Almirall R and nter | Otal R.,Almirall R and nter | And 15 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2012

Abediterol is a novel potent, long-acting inhaled β2- adrenoceptor agonist in development for the treatment of asthma and chronic obstructive pulmonary disease. Abediterol shows subnanomolar affinity for the human β2-adrenoceptor and a functional selectivity over β1-adrenoceptors higher than that of formoterol and indacaterol in both a cellular model with overexpressed human receptors and isolated guinea pig tissue. Abediterol is a full agonist at the human β2- adrenoceptor (Emax = 91 ± 5% of the maximal effect of isoprenaline). The potency and onset of action that abediterol shows in isolated human bronchi (EC50 = 1.9 ± 0.4 nM; t1/2 onset = 7-10 min) is not significantly different from that of formoterol, but its duration of action (t1/2 ∼ 690 min) is similar to that of indacaterol. Nebulized abediterol inhibits acetylcholine-induced bronchoconstriction in guinea pigs in a concentration-dependent manner, with higher potency and longer duration of action (t1/2 = 36 h) than salmeterol (t1/2 = 6 h) and formoterol (t1/2 = 4 h) and similar duration of action to indacaterol up to 48 h. In dogs, the bronchoprotective effect of abediterol is more sustained than that of salmeterol and indacaterol at doses without effects on heart rate, thus showing a greater safety margin (defined as the ratio of dose increasing heart rate by 5% and dose inhibiting bronchospasm by 50%) than salmeterol, formoterol, and indacaterol (5.6 versus 3.3, 2.2, and 0.3, respectively). In conclusion, our results suggest that abediterol has a preclinical profile for once-daily dosing in humans together with a fast onset of action and a favorable cardiovascular safety profile. Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics.


Southworth T.,University of Manchester | Plumb J.,University of Manchester | Gupta V.,University of Manchester | Pearson J.,University of Manchester | And 4 more authors.
Respiratory Research | Year: 2016

Background: Phosphatidylinositol 3-kinase delta (PI3Kδ) and Janus-activated kinases (JAK) are both novel anti-inflammatory targets in asthma that affect lymphocyte activation. We have investigated the anti-inflammatory effects of PI3Kδ and JAK inhibition on cytokine release from asthma bronchoalveolar lavage (BAL) cells and T-cell activation, and measured lung PI3Kδ and JAK signalling pathway expression. Method: Cells isolated from asthma patients and healthy subjects were treated with PI3Kδ or JAK inhibitors, and/or dexamethasone, before T-cell receptor stimulation. Levels of IFNγ, IL-13 and IL-17 were measured by ELISA and flow cytometry was used to assess T-cell activation. PI3Kδ, PI3Kγ, phosphorylated protein kinase B (pAKT) and Signal Transducer and Activator of Transcription (STAT) protein expression were assessed by immunohistochemistry in bronchial biopsy tissue from asthma patients and healthy subjects. PI3Kδ expression in BAL CD3 cells was measured by flow cytometry. Results: JAK and PI3Kδ inhibitors reduced cytokine levels from both asthma and healthy BAL cells. Combining dexamethasone with either a JAK or PI3Kδ inhibitor showed an additive anti-inflammatory effect. JAK and PI3Kδ inhibitors were shown to have direct effects on T-cell activation. Immunohistochemistry showed increased numbers of PI3Kδ expressing cells in asthma bronchial tissue compared to controls. Asthma CD3 cells in BAL expressed higher levels of PI3Kδ protein compared to healthy cells. Conclusions: Targeting PI3Kδ or JAK may prove effective in reducing T-cell activation and the resulting cytokine production in asthma. © 2016 The Author(s).


Singh D.,University of Manchester | Magnussen H.,Pulmonary Research Institute at Hospital Grosshansdorf | Kirsten A.,Pulmonary Research Institute at Hospital Grosshansdorf | Mindt S.,Klinische Forschung Hamburg GmbH | And 4 more authors.
Pulmonary Pharmacology and Therapeutics | Year: 2012

This Phase IIb, double-blind, double-dummy, placebo- and active-comparator-controlled crossover study (ClinicalTrials.gov identifier: NCT01120093) assessed efficacy and safety of three doses of aclidinium bromide in patients with moderate to severe chronic obstructive pulmonary disease. Patients were randomised to one of five treatment sequences each consisting of twice-daily (BID) aclidinium 100 μg, 200 μg, 400 μg (via Genuair ®*), formoterol 12 μg (via Aerolizer ®) and matched placebo for 7 days, with a 5- to 9-day washout period. Primary endpoint was mean change from baseline in forced expiratory volume in 1 s (FEV 1) normalised area under the curve (AUC) 0-12 on Day 7. Secondary endpoints were: change from baseline in FEV 1 normalised AUC 12-24, FEV 1 normalised AUC 0-24 and morning pre-dose FEV 1 on Day 7. Adverse events were monitored throughout the study. Of 79 randomised patients, 68 (86.1%) completed the study. After 7 days of treatment, aclidinium and formoterol produced statistically significantly greater changes from baseline in FEV 1 normalised AUC 0-12 vs placebo (p < 0.0001). FEV 1 normalised AUC 12-24, FEV 1 normalised AUC 0-24, and morning pre-dose FEV 1 were also statistically significantly greater with all aclidinium doses vs placebo (p < 0.0001). Improvements in primary and secondary endpoints were statistically significantly greater with aclidinium 400 μg vs 100 μg. The safety profile of aclidinium was comparable to placebo. These results demonstrated that twice-daily aclidinium produced dose-dependent clinically meaningful improvements in FEV 1 compared with placebo. This study also confirmed the use of an aclidinium BID dosing regimen and established aclidinium 200 μg and 400 μg as suitable doses for further investigation in Phase III trials. © 2012 Elsevier Ltd.


Buil M.A.,Almirall R and nter | Calbet M.,Almirall R and nter | Castillo M.,Almirall Barcelona Science Park Unit | Castro J.,Almirall R and nter | And 11 more authors.
European Journal of Medicinal Chemistry | Year: 2016

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. © 2016 Elsevier Masson SAS. All rights reserved.


Andres M.,Almirall R and nter | Buil M.A.,Almirall R and nter | Calbet M.,Almirall R and nter | Casado O.,Almirall Barcelona Science Park Unit | And 8 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2014

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. © 2014 Elsevier Ltd. All rights reserved.


Ramis I.,Almirall R and nter | Otal R.,Almirall R and nter | Carreno C.,Almirall R and nter | Domenech A.,Almirall R and nter | And 8 more authors.
Pharmacological Research | Year: 2015

Spleen tyrosine kinase (Syk) is essential for signal transduction of immunoreceptors. Inhibition of Syk abrogates mast cell degranulation and B cell responses. We hypothesized that Syk inhibition in the lung by inhaled route could block airway mast cells degranulation and the early asthmatic response without the need of systemic exposure. We discovered LAS189386, a novel Syk inhibitor with suitable properties for inhaled administration. The aim of this study was to characterize the in vitro and in vivo profile of LAS189386. The compound was profiled in Syk enzymatic assay, against a panel of selected kinases and in Syk-dependent cellular assays in mast cells and B cells. Pharmacokinetics and in vivo efficacy was assessed by intratracheal route. Airway resistance and mast cell degranulation after OVA challenge was evaluated in an ovalbumin-sensitized Brown Norway rat model. LAS189386 potently inhibits Syk enzymatic activity (IC50 7.2 nM), Syk phosphorylation (IC50 41 nM), LAD2 cells degranulation (IC50 56 nM), and B cell activation (IC50 22 nM). LAS189386 inhibits early asthmatic response and airway mast cell degranulation without affecting systemic mast cells. The present results support the hypothesis that topical inhibition of Syk in the lung, without systemic exposure, is sufficient to inhibit EAR in rats. Syk inhibition by inhaled route constitutes a promising therapeutic option for asthma. © 2015 Elsevier Ltd. All rights reserved.


Andres M.,Almirall R and nter | Bravo M.,Almirall R and nter | Buil M.A.,Almirall R and nter | Calbet M.,Almirall R and nter | And 9 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2013

High throughput screening identified the pyrazole-4-acetic acid substructure as CRTh2 receptor antagonists. Optimisation of the compounds uncovered a tight SAR but also identified some low nanomolar inhibitors. © 2013 Elsevier Ltd. All rights reserved.


Alonso J.A.,Almirall R and nter | Andres M.,Almirall R and nter | Bravo M.,Almirall R and nter | Buil M.A.,Almirall R and nter | And 14 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2014

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. © 2014 Elsevier Ltd. All rights reserved.


Gavalda A.,Almirall R and nter | Ramos I.,Almirall R and nter | Carcasona C.,Almirall R and nter | Calama E.,Almirall R and nter | And 8 more authors.
Pulmonary Pharmacology and Therapeutics | Year: 2014

This study characterised the invitro and invivo profiles of two novel long-acting muscarinic antagonists, aclidinium bromide and glycopyrronium bromide, using tiotropium bromide and ipratropium bromide as comparators. All four antagonists had high affinity for the five muscarinic receptor sub-types (M1-M5); aclidinium had comparable affinity to tiotropium but higher affinity than glycopyrronium and ipratropium for all receptors. Glycopyrronium dissociated faster from recombinant M3 receptors than aclidinium and tiotropium but more slowly than ipratropium; all four compounds dissociated more rapidly from M2 receptors than from M3 receptors. Invitro, aclidinium, glycopyrronium and tiotropium had a long duration of action at native M3 receptors (>8h versus 42min for ipratropium). Invivo, all compounds were equi-potent at reversing acetylcholine-induced bronchoconstriction. Aclidinium, glycopyrronium and ipratropium had a faster onset of bronchodilator action than tiotropium. Aclidinium had a longer duration of action than glycopyronnium (time to 50% recovery of effect [t1/2 offset]=29h and 13h, respectively); these compare with a t1/2 offset of 64h and 8h for tiotropium and ipratropium, respectively. Aclidinium was less potent than glycopyrronium and tiotropium at inhibiting salivation in conscious rats (dose required to produce half-maximal effect [ED50]=38, 0.74 and 0.88μg/kg, respectively) and was more rapidly hydrolysed in rat, guinea pig and human plasma compared with glycopyrronium or tiotropium. These results indicate that while aclidinium and glycopyrronium are both potent antagonists at muscarinic receptors with similar kinetic selectivity for M3 receptors versus M2, aclidinium has a longer dissociation half-life at M3 receptors and a longer duration of bronchodilator action invivo than glycopyrronium. The rapid plasma hydrolysis of aclidinium, coupled to its kinetic selectivity, may confer a reduced propensity for systemic anticholinergic side effects with aclidinium versus glycopyrronium and tiotropium. © 2014 The Authors.

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