Michael Yeadon's scientific contributions
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Publications (13)
We wished to identify a CNS-sparing histamine H3receptor antagonist for the treatment of allergic rhinitis. We aimed for compounds with low permeability, high solubility, that were substrates for the BBB efflux transporters MDR-1 and BCRP. The key lead PF-0868087 demonstrated over a 10-fold CNS-sparing profile in 2 preclinical species.
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, t...
Antisense oligonucleotides (ASOs) and small interfering RNA (siRNA) promise specific correction of disease-causing gene expression. Therapeutic implementation, however, has been forestalled by poor delivery to the appropriate tissue, cell type, and subcellular compartment. Topical administration is considered to circumvent these issues. The availab...
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 bioavailab...
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...
‘Inhalation by design’ concepts were developed to create novel dual pharmacology β-2 agonists-M3 antagonists, for the treatment of chronic obstructive pulmonary disorder. A key feature of this work is the combination of balanced potency and pharmacological duration with optimised glucuronidation through the incorporation of metabolically vulnerable...
A novel tertiary amine series of potent muscarinic M(3) receptor antagonists are described that exhibit potential as inhaled long-acting bronchodilators for the treatment of chronic obstructive pulmonary disease. Geminal dimethyl functionality present in this series of compounds confers very long dissociative half-life (slow off-rate) from the M(3)...
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....
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. The pharmacological and pharmacokinetic SAR of a series of inhaled A(2A) agoni...
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 ef...
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 clearanc...
Asthma affects 300 million people worldwide and continues to be a major cause of morbidity and mortality. Disease relevant animal models of asthma are required for benchmarking of novel therapeutic mechanisms in comparison to established clinical approaches. We demonstrate that chronic exposure of mice to house dust mite (HDM) extract results in al...
Citations
... PF-610355 was developed by medicinal chemists at Pfizer who were attempting to synthesize novel, once daily inhaled β 2 agonists. 74 PF-610355 has a β 2 EC50 of 0.26 nM and is approximately 4-fold more potent than salmeterol with a prolonged duration of action in the in vitro guinea pig trachea contraction model. 74 In an in vivo canine intravenous acetylcholine bronchoprovocation model, PF-610355 was an equipotent bronchodilator compared with formoterol and more potent than salmeterol. ...
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... Tiotropium was considered a promising LAMA for dual bronchodilator (LAMA þ LABA) therapy because of its favorable efficacy. Further, tiotropium may also improve left ventricular function in patients with COPD and chronic heart failure and may have anti-inflammatory effects 48,49 . Additionally, with a similar duration of action and complementary mechanism of action, olodaterol was considered a viable LABA to pair with tiotropium in an FDC. ...
... For example, the quinazoline-based inhibitors gefitinib and lapatinib have K i app values for EGFR of 0.4 and 3 nM, respectively, but while gefitinib has a residence time of <14 min, lapatinib has a residence time of 430 min. 34 Other examples include antagonists of the muscarinic M3 receptor, 35 antagonists of the chemoattractant receptor-homologous The driving force for binding is given by the difference in free energy between E+I and E-I (ΔG K d ). Experimental measurements of the equilibrium dissociation constant K d , or parameters such as IC 50 values, provide a quantitative estimate of the thermodynamics for binding. ...
Reference: Drug-Target Kinetics in Drug Discovery
... Inhaled corticosteroids (ICS) are the most common maintenance drug used in patients with asthma. ICS's antiinflammatory properties decrease lung inflammation and improve overall allergic asthma lung symptoms (De Graaf-In't Veld et al. 1995;Boulet et al. 2000;Gershman et al. 2000;Teper et al. 2004;Lee et al. 2008;Ulrich et al. 2008;Wakahara et al. 2008;Riesenfeld et al. 2010;Stempel et al. 2016). Given their effectiveness, they are prescribed at higher doses with increasing asthma severity and when lower doses do not control symptoms (Lemanske et al. 2010;Wechsler et al. 2019). ...
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... 26 The inhibition of early and late inflammatory reactions by selective A2AR agonists has been confirmed in in vivo models of respiratory system diseases, 27 for some of which corticosteroid therapy has not yet been sufficiently substantiated. 28 Encouraging results have also been obtained in animal models of bowel diseases 29,30 ; and in in vivo and clinical studies in several autoimmune diseases, 31 for example, rheumatic diseases 32,33 ; for example, adenosine was shown to reduce inflammatory cell infiltrates and enhance T reg activity in animal models of obesity by reducing adipose tissue inflammation and improving glucose homeostasis. 34 Furthermore, A2AR activation in bone marrowderived cells exerts a protective effect against ischemia/reperfusion injury in several organs [35][36][37][38][39] and sepsis. ...
... Lung PS ASOs have been explored as therapeutics for treating pulmonary diseases associated with genetic conditions such as cystic fibrosis (CF) and various lung cancers [41,42]. The local administration of ASOs by aerosol delivery or intranasal dosing result in significant accumulation in the lumen of small and large airways, across both lung epithelial and endothelial cells [43,44]. ASOs are well tolerated in rodent and non-human primate models and human subjects [43,45,46], and showed negligible systemic activity, ensuring their safety as locally administered therapeutics for lung diseases [45,47]. ...
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... The safety and efficacy of UK-432097 in chronic obstructive pulmonary disease was terminated as of 17 March 2009-see (http://www.clinicaltrials.gov). However, the compound showed carcinogenic activity and, thus, unsatisfactory results in Phase II clinical trials [13,19]. The prediction of pharmacokinetic, toxicological, and stereo-electronic features by in silico studies would be an interesting way for choosing drugs with inhibitory potential, such as demonstrated in previous studies [17,20,21]. ...
... Drug development of specific cPLA2 inhibitors for treatment of asthma and allergic diseases has been underway for the past two decades, with many orally-bioavailable compounds entering human clinical trials [84][85][86] (Figure 1). For example, a topical solution of the cPLA2 inhibitor ZPL-521 has now completed a phase IIb clinical trial for treatment of atopic dermatitis [48](NCT02795832). ...
... 71 CHF6297 is a potent p38 inhibitor, available as a dry powder preparation, which is undergoing clinical evaluation for inhaled therapy of COPD. 8 Another p38 MAPK inhibitor that has been developed as a dry powder inhaler is PF-03715455, 72 currently under investigation for treatment of patients with moderate or severe COPD. 8 The most common adverse events observed in the above clinical trials were nasopharyngitis, headache, diarrhoea, nausea, and arthralgia. ...
