Characterisation and Profiling of Standard Atopic Dermatitis Therapies in a Chronic Dermatitis Murine Model Induced by Oxazolone.

Atopic dermatitis (AD) is a common inflammatory skin disorder characterised by hypersensitivity to allergens, eczematous lesions and pruritus. The aim of this study was to comprehensively characterise a murine model of dermatitis and assess the similarity with the human disease, as well as to profile clinically relevant AD therapies. Four repeated topical administrations of oxazolone in the auricular skin of sensitised mice induced morphological features compatible with AD, including redness and swelling, as well as histological changes typical of spongiotic (eczematous) dermatitis and increased plasmatic IgE.

Physiologic Effects of Housing Rats in Metabolic Cages.

Currently, metabolic cages (MC) are the only way to achieve serial sampling of urine and feces in rodents. However, the use of this caging creates a dramatic change from an animal's usual microenvironment. Here we sought to examine the effect of MC on physiologic parameters that are stress-responsive in rats.

Pharmacological Profile of AZD8871 (LAS191351), a Novel Inhaled Dual M Receptor Antagonist/ -Adrenoceptor Agonist Molecule with Long-Lasting Effects and Favorable Safety Profile.

AZD8871 is a novel muscarinic antagonist and -adrenoceptor agonist in development for chronic obstructive pulmonary disease. This study describes the pharmacological profile of AZD8871 in in vitro and in vivo assays. AZD8871 is potent at the human M receptor (pIC in binding assays: 9.

4-Amino-7,8-dihydro-1,6-naphthyridin-5(6 H)-ones as Inhaled Phosphodiesterase Type 4 (PDE4) Inhibitors: Structural Biology and Structure-Activity Relationships.

Rational design of a novel template of naphthyridinones rapidly led to PDE4 inhibitors with subnanomolar enzymatic potencies. X-ray crystallography confirmed the binding mode of this novel template. We achieved compounds with double-digit picomolar enzymatic potencies through further structure-based design by targeting both the PDE4 enzyme metal-binding pocket and occupying the solvent-filled pocket.

Abediterol (LAS100977), an inhaled long-acting β-adrenoceptor agonist, has a fast association rate and long residence time at receptor.

This study describes the association rate and residence time of abediterol, a novel long-acting β-adrenoceptor agonist (LABA) in Phase II development for treatment of asthma and COPD, in comparison with indacaterol, olodaterol, vilanterol and salmeterol, for both human β- and β-adrenoceptors. Abediterol association and dissociation rates were monitored directly by using its tritiated form. Moreover, association was determined indirectly using experimental K and k obtained from assays performed with unlabelled compound.

Pharmacological preclinical characterization of LAS190792, a novel inhaled bifunctional muscarinic receptor antagonist /β-adrenoceptor agonist (MABA) molecule.

LAS190792 is a novel muscarinic antagonist and β-adrenoceptor agonist in development for chronic respiratory diseases. This study investigated the pharmacological profile of LAS190792 in comparison to batefenterol, tiotropium, indacaterol and olodaterol. LAS190792 is potent at the human M receptor (pIC: 8.

Biphenyl Pyridazinone Derivatives as Inhaled PDE4 Inhibitors: Structural Biology and Structure-Activity Relationships.

Cyclic nucleotide cAMP is a ubiquitous secondary messenger involved in a plethora of cellular responses to biological agents involving activation of adenylyl cyclase. Its intracellular levels are tightly controlled by a family of cyclic nucleotide degrading enzymes, the PDEs. In recent years, cyclic nucleotide phosphodiesterase type 4 (PDE4) has aroused scientific attention as a suitable target for anti-inflammatory therapy in respiratory diseases, particularly in the management of asthma and COPD.

Selective Sphingosine 1-Phosphate Receptor 1 Agonist Is Protective Against Ischemia/Reperfusion in Mice.

Background And Purpose: Growing evidence supports that the immunomodulatory drug fingolimod is protective in stroke. Fingolimod binds to 4 of 5 sphingosine-1-phosphate (S1P) receptors and, among other actions, it induces lymphopenia. In this study, we investigated whether a selective S1P1 agonist is protective in experimental stroke.

In vitro and in vivo preclinical profile of abediterol (LAS100977), an inhaled long-acting β2-adrenoceptor agonist, compared with indacaterol, olodaterol and vilanterol.

Abediterol is a novel long-acting β2-adrenoceptor agonist (LABA) currently in development for once-daily combination maintenance therapy of asthma and COPD. This study investigated the preclinical profile of abediterol in terms of affinity, potency, selectivity, duration of action and cardiac effects in comparison to the marketed once-daily LABAs indacaterol, olodaterol and vilanterol. Abediterol was the compound with the highest in vitro potency for dog, guinea pig and human β2-adrenoceptors.

Effects of Changing to Individually Ventilated Caging on Guinea Pigs (Cavia porcellus).

The goal of this study was to evaluate the effect of changing to IVC housing on guinea pigs by recording several physiologic parameters in guinea pigs housed sequentially in open-top cages (OTC) and IVC. To register heart rate and locomotor activity, 10 male Dunkin-Hartley guinea pigs implanted with telemetric transmitters were moved from OTC to new, freshly prepared OTC or IVC and subsequently monitored by telemetry during the 4 d after the first cage change. Body weight and food consumption were measured twice during the study.

Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinyl amides as potent and long acting muscarinic antagonists.

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.

Pharmacological characterization of the interaction between aclidinium bromide and formoterol fumarate on human isolated bronchi.

Long-acting muscarinic receptor antagonists (LAMAs) and long-acting β2-adrenoceptor agonists (LABAs) cause airway smooth muscle (ASM) relaxation via different signal transduction pathways, but there are limited data concerning the interaction between these two drug classes on human bronchi. The aim of this study was to investigate the potential synergistic interaction between aclidinium bromide and formoterol fumarate on the relaxation of human ASM. We evaluated the influence of aclidinium bromide and formoterol fumarate on the contractile response induced by acetylcholine or electrical field stimulation (EFS) on human isolated airways (segmental bronchi and bronchioles).

The in vitro and in vivo profile of aclidinium bromide in comparison with glycopyrronium bromide.

This study characterised the in vitro and in vivo 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.

Effects of aclidinium bromide in a cigarette smoke-exposed Guinea pig model of chronic obstructive pulmonary disease.

Long-acting muscarinic antagonists are widely used to treat chronic obstructive pulmonary disease (COPD). In addition to bronchodilation, muscarinic antagonism may affect pulmonary histopathological changes. The effects of long-acting muscarinic antagonists have not been thoroughly evaluated in experimental models of COPD induced by chronic exposure to cigarette smoke (CS).

Phosphodiesterase-4 inhibitors: a review of current developments (2010 - 2012).

Introduction: At last, after many years of research, roflumilast has become the first oral phosphodiesterase-4 inhibitor to be approved by the medical agencies as an add-on therapy for chronic obstructive pulmonary disease. A second compound, apremilast is targeted for submission of new drug application for the treatment of psoriasis in the second half of 2013. These compounds represent a breakthrough and a reward in the field after the many failures to date in clinical development.

Aclidinium inhibits cigarette smoke-induced lung fibroblast-to-myofibroblast transition.

Cigarette smoking contributes to lung remodelling in chronic obstructive pulmonary disease (COPD). As part of this remodelling, peribronchiolar fibrosis is observed in the small airways of COPD patients and contributes to airway obstruction. Fibroblast-to-myofibroblast transition is a key step in peribronchiolar fibrosis formation.

Pharmacological characterization of abediterol, a novel inhaled β(2)-adrenoceptor agonist with long duration of action and a favorable safety profile in preclinical models.

Abediterol is a novel potent, long-acting inhaled β(2)-adrenoceptor agonist in development for the treatment of asthma and chronic obstructive pulmonary disease. Abediterol shows subnanomolar affinity for the human β(2)-adrenoceptor and a functional selectivity over β(1)-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 β(2)-adrenoceptor (E(max) = 91 ± 5% of the maximal effect of isoprenaline).

Aclidinium bromide, a novel long-acting muscarinic antagonist for COPD with improved preclinical renal and urinary safety profile.

Aims: Aclidinium bromide is a novel, long-acting, inhaled muscarinic antagonist currently in registration phase for the treatment of chronic obstructive pulmonary disease. Since urinary difficulty and retention have been reported for anticholinergic agents such as tiotropium and ipratropium, it is important to examine the preclinical urinary and renal safety profile of aclidinium.

Main Methods: The effect of aclidinium on urine and electrolyte excretion, renal function and voiding cystometry was analysed in conscious water-loaded Wistar rats (10-1000 μg/kg, s.

Aclidinium inhibits human lung fibroblast to myofibroblast transition.

Background: Fibroblast to myofibroblast transition is believed to contribute to airway remodelling in lung diseases such as asthma and chronic obstructive pulmonary disease. This study examines the role of aclidinium, a new long-acting muscarinic antagonist, on human fibroblast to myofibroblast transition.

Methods: Human bronchial fibroblasts were stimulated with carbachol (10(-8) to 10(-5) M) or transforming growth factor-β1 (TGF-β1; 2 ng/ml) in the presence or absence of aclidinium (10(-9) to 10(-7) M) or different drug modulators for 48 h.

Synthesis and biological activity of pyrido[3',2':4,5]furo[3,2-d]pyrimidine derivatives as novel and potent phosphodiesterase type 4 inhibitors.

A series of pyrido[3',2':4,5]furo[3,2-d]pyrimidines (PFP) were synthesized and tested for phosphodiesterase type 4 (PDE4) inhibitory activity, with the potential to treat asthma and chronic obstructive pulmonary disease (COPD). Structure-activity relationships within this series, leading to an increase of potency on the enzyme, is presented. Both gem-dimethylcyclohexyl moieties fused to the pyridine ring and the substitution at the 5 position of the PFP scaffold, proved to be key elements in order to get a high affinity in the enzyme.

Inhaled muscarinic antagonists for respiratory diseases: a review of patents and current developments (2006 - 2010).

Introduction: Because tiotropium has demonstrated clinical benefits as a long-term maintenance treatment for chronic obstructive pulmonary disease (COPD), the number of patent applications of new chemical entities with antimuscarinic activity has significantly increased, along with the number of compounds that have reached clinical development.

Areas Covered: This review summarizes the current status of long-acting muscarinic antagonists (LAMA) in clinical development for COPD, and the associated patent literature since 2006, with a focus on new chemical entities.

Expert Opinion: In recent years, companies have taken different approaches to obtain compounds with high potency, long duration of action and minimal systemic exposure.

Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinyl carbamates as potent and long acting muscarinic antagonists.

Novel quaternary ammonium derivatives of N,N-disubstituted (3R)-quinuclidinyl carbamates have been identified as potent M(3) muscarinic antagonists with long duration of action in an in vivo model of bronchoconstriction. These compounds have also presented a high level of metabolic transformation (human liver microsomes). The synthesis, structure-activity relationships and biological evaluation of these compounds are reported.

Discovery of substituted phenyl urea derivatives as novel long-acting β2-adrenoreceptor agonists.

The synthesis of diverse functionalized ureas in a semi-parallel fashion is described, as well as their β(1)/β(2)-adrenergic activities and the corresponding structure-activity relationship (SAR). We have focused on lipophilicity and duration of action, and we have discovered a strong correlation in this series of molecules. A quantitative structure-activity relationship (QSAR) analysis will be presented that quantifies this relationship.