A5065743554- Asthma and respiratory diseases
- Phosphodiesterase function and regulation
- Phenothiazines and Benzothiazines Synthesis and Activities
- Receptor Mechanisms and Signaling
- Mast cells and histamine
- Chronic Obstructive Pulmonary Disease (COPD) Research
- Respiratory and Cough-Related Research
- Adenosine and Purinergic Signaling
- Synthesis and Biological Evaluation
- Neuropeptides and Animal Physiology
- Synthesis and biological activity
- Nitric Oxide and Endothelin Effects
- Glycogen Storage Diseases and Myoclonus
- Pharmacological Effects and Assays
- Protein Kinase Regulation and GTPase Signaling
- Inhalation and Respiratory Drug Delivery
- Metabolism, Diabetes, and Cancer
- Ion channel regulation and function
- Migraine and Headache Studies
- Air Quality and Health Impacts
- Neuroscience of respiration and sleep
- Streptococcal Infections and Treatments
- Biochemical and Molecular Research
- Metabolism and Genetic Disorders
- Microfluidic and Capillary Electrophoresis Applications
AstraZeneca (Sweden)
2019
Almirall (Spain)
2004-2015
Universidade de Santiago de Compostela
2007
Instituto de Química Médica
2000
Centre d’Investigació i Desenvolupament
2000
Centro de Investigación y Desarrollo
2000
Universitat de València
1999
University of Florence
1997-1999
Palobiofarma (Spain)
1998
Consejo Superior de Investigaciones Científicas
1998
Aclidinium bromide is a novel potent, long-acting inhaled muscarinic antagonist in development for the treatment of chronic obstructive pulmonary disease. showed subnanomolar affinity five human receptors (M<sub>1</sub>–M<sub>5</sub>). [<sup>3</sup>H]Aclidinium dissociated slightly faster from M<sub>2</sub> and M<sub>3</sub> than [<sup>3</sup>H]tiotropium but much more slowly [<sup>3</sup>H]ipratropium. Its association rate receptor was similar to [<sup>3</sup>H]ipratropium 2.6 times...
We have investigated the role of cyclic nucleotide phosphodiesterase IV (PDEIV) in relaxation human bronchus and guinea‐pig trachea vitro guinea‐pigs vivo . Functional studies showed that selective PDE inhibitors, rolipram denbufylline, relaxed preparations Two clinically used xanthine non‐selective theophylline pentoxifylline, were also effective these preparations, but much less potent than agents used. The rank order potency for four inhibitors both species was similar. Biochemical...
The objective of this work was to discover a novel, long-acting muscarinic M3 antagonist for the inhaled treatment chronic obstructive pulmonary disease (COPD), with potentially improved risk−benefit profile compared current antimuscarinic agents. A series novel quaternary ammonium derivatives (3R)-quinuclidinol esters were synthesized and evaluated. On basis its overall profile, (3R)-3-{[hydroxy(di-2-thienyl)acetyl]oxy}-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (aclidinium...
Abediterol is a novel potent, long-acting inhaled β(2)-adrenoceptor agonist in development for the treatment of asthma and chronic obstructive pulmonary disease. shows subnanomolar affinity human functional selectivity over β(1)-adrenoceptors higher than that formoterol indacaterol both cellular model with overexpressed receptors isolated guinea pig tissue. full at (E(max) = 91 ± 5% maximal effect isoprenaline). The potency onset action abediterol bronchi (EC(50) 1.9 0.4 nM; t½ 7-10 min) not...
This study characterised the in vitro and vivo profiles of two novel long-acting muscarinic antagonists, aclidinium bromide glycopyrronium bromide, using tiotropium ipratropium as comparators. All four antagonists had high affinity for five receptor sub-types (M1-M5); comparable to but higher than all receptors. Glycopyrronium dissociated faster from recombinant M3 receptors more slowly ipratropium; compounds rapidly M2 In vitro, aclidinium, a long duration action at native (>8 h versus 42...
Adenosine is produced during inflammation and modulates different functional activities in macrophages. In murine bone marrow-derived macrophages, adenosine inhibits M-CSF-dependent proliferation with an IC50 of 45 microM. Only specific agonists that can activate A2B receptors such as 5'-N-ethylcarboxamidoadenosine, but not those active on A1 (N6-(R)-phenylisopropyladenosine), A2A ([p-(2-carbonylethyl)phenylethylamino]-5'-N-ethylcarboxamido adenosine), or A3...
A series of 6-aryl-4,5-heterocyclic-fused pyridazinones were designed and synthesized as selective phosphodiesterase (PDE) IV inhibitors. Biological evaluation these compounds demonstrated a good selectivity profile toward the PDE family greatly attenuated affinity for Rolipram high-affinity binding site that seems to be responsible undesiderable side effects. Structure−activity relationships (SARs) studies showed presence an ethyl group at pyridazine N-2 is associated with best potency profile.
The synthesis of a new family benzyl derivatives 2,1,3-benzo- and benzothieno[3,2-a]thiadiazine 2,2-dioxides was achieved. biological data revealed the first heterocyclic compounds with PDE 7 inhibitory properties appearing to be objective for treatment T-cell-dependent disorders. IC50 values or percent inhibition against were calculated by testing them human recombinant expressed in S. cerevisiae. In this expression system only cyclic nucleotide hydrolyzing activity present cell extracts...
Selective phosphodiesterase 4 (PDE4) inhibitors are of potential interest in the treatment asthma. We examined effects alkaloid S‐(+)‐glaucine, a PDE4 inhibitor, on human isolated bronchus and granulocyte function. Glaucine selectively inhibited from polymorphonuclear leukocytes (PMN) non‐competitive manner ( K i =3.4 μ M ). displaced [ 3 H]‐rolipram its high‐affinity binding sites rat brain cortex membranes (IC 50 ∼100 spontaneous histamine‐induced tone (pD 2 ∼4.5). (10 ) did not potentiate...
This study aimed to investigate the 5‐hydroxytryptamine (5‐HT) receptors mediating contraction of ring preparations isolated from human pulmonary arteries and veins. In functional studies, responses 5‐HT, sumatriptan, ergotamine, serotonin‐ O ‐carboxymethyl‐glycyl‐tyrosinamide (SCMGT), α‐methyl 5‐HT (α‐Me) 2‐methyl (2‐Me) were studied with WAY100635, GR127935, ritanserin, zacopride SB204070 as antagonists. All agonists produced concentration‐dependent contractions artery vein preparations....
A series of pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidines (PTP) has been synthesized and tested as phosphodiesterase IV inhibitors (PDE4), a target for the treatment asthma chronic obstructive pulmonary disease (COPD). Structure−activity relationships within this series, leading to an increase potency on enzyme, are presented. The gem-dimethylcycloalkyl moiety fused pyridine ring proved be key element scaffold in order get higher affinity enzyme.
The responses of the electrically‐driven right ventricle strip guinea‐pig heart to diazepam were recorded in absence and presence different selective cyclic nucleotide phosphodiesterase (PDE) inhibitors. Diazepam, at concentrations ranging from 1 μ M 100 , was devoid effect on contractile force this preparation. Conversely, (5 –100 ) produced a consistent positive inotropic response concentration (1 ), that without diazepam, either PDE 3 inhibitors milrinone or SK&F 94120, but not 4...
A novel series of N-heteroaryl 4'-(2-furyl)-4,5'-bipyrimidin-2'-amines has been identified as potent and selective A(2B) adenosine receptor antagonists. In particular, compound 5 showed high affinity for the (Ki = 17 nM), good selectivity (IC(50): A(1) > 1000 nM, A(2A) 2500 A3 displayed a favorable pharmacokinetic profile in preclinical species, efficacy functional vitro models.