Michael Yeadon

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This paper describes the identification and optimization of a novel series of DFG-out binding p38 inhibitors as inhaled agents for the treatment of chronic obstructive pulmonary disease. Structure based drug design and "inhalation by design" principles have been applied to the optimization of the lead series exemplied by compound 1a. Analogues have been(More)
Mucus hypersecretion is a feature of several respiratory diseases and frequently leads to obstruction of small airways where the principal source of mucous glycoproteins (mucins), the major macromolecular constituents of mucus, are goblet cells. Hence, inhibition of mucin secretion from these cells may be clinically beneficial. In this study, we have(More)
Asthma is a chronic inflammatory lung disease with considerable unmet medical needs for new and effective therapies. Cytosolic phospholipase A(2)α (cPLA(2)α) is the rate-limiting enzyme that is ultimately responsible for the production of eicosanoids implicated in the pathogenesis of asthma. We investigated a novel cPLA(2)α inhibitor, PF-5212372, to(More)
The actions of BW B70C, an orally available, biologically persistent and selective inhibitor of arachidonic acid 5-lipoxygenase, have been examined in two systems of anaphylaxis in actively sensitised guinea-pigsin vivo. In anaesthetised, artificially ventilated animals pretreated with mepyramine and indomethacin to leave only the(More)
In this Letter we present data for a novel series of ICS for the treatment of asthma. 'Inhalation by design' principles have been applied to a series of highly potent steroidal GR agonists, with a focus on optimising the potential therapeutic index in human. Pharmacokinetic properties were tuned with high intrinsic clearance and low oral bioavailability in(More)
The long acting inhaled muscarinic antagonist tiotropium (Spiriva) improves lung function in patients with COPD. In addition, tiotropium reduces exacerbation frequency, dyspnoea and improves exercise capacity. As the latter has been associated with airway inflammation then this suggests that, in addition to the well-known anti-bronchoconstrictor effect,(More)
There is some evidence that nitric oxide synthase (NOS) is induced in the lungs of patients with allergic asthma, but the mechanism of this is not understood. The aim of the present study was to investigate whether the levels of NOS in rat lung could be altered by exposure of the animals to aerosols of allergen (ovalbumin). Brown-Norway rats were actively(More)
COPD is a major cause of mortality in the western world. A(2A) agonists are postulated to reduce the lung inflammation that causes COPD. The cardiovascular effects of A(2A) agonists dictate that a compound needs to be delivered by inhalation to be therapeutically useful. A strategy of minimizing side-effect liability by maximizing systemic clearance was(More)
A novel series of potent and selective sulfonamide derived β(2)-adrenoreceptor agonists are described that exhibit potential as inhaled ultra-long-acting bronchodilators for the treatment of asthma and chronic obstructive pulmonary disease. Analogues from this series mediate very long-lasting smooth muscle relaxation in guinea pig tracheal strips. The(More)
A method has been established for measurement of tracheal secretions in anaesthetized, ventilated guinea-pigs. The upper trachea was cannulated and perfused with saline. The perfusate was analysed for protein using the Lowry assay and for glycoconjugates ('mucus') by a procedure generating a fluorophore from fucose moieties in the sample. Intravenously(More)