Molecular hybridization yields triazole bronchodilators for the treatment of COPD.

A 1,2,4-triazole motif was employed as a bioisostere for the ester commonly used in muscarinic antagonists, and subsequent integrative conjugation to a β2 agonist quinolinone furnished a new class of bifunctional MABAs for the treatment of COPD. Medicinal chemistry optimization using the principles of 'inhalation by design' furnished a clinical candidate with desirable pharmacological, pharmacokinetic and biopharmaceutical properties.

Inhalation by design: novel tertiary amine muscarinic M₃ receptor antagonists with slow off-rate binding kinetics for inhaled once-daily treatment of chronic obstructive pulmonary disease.

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) receptor that mediates very long-lasting smooth muscle relaxation in guinea pig tracheal strips. Optimization of pharmacokinetic properties was achieved by combining rapid oxidative clearance with targeted introduction of a phenolic moiety to secure rapid glucuronidation.

Inhalation by design: dual pharmacology β-2 agonists/M3 antagonists for the treatment of COPD.

This paper describes the successful design and development of dual pharmacology β-2 agonists-M3 antagonists, for the treatment of chronic obstructive pulmonary disorder using the principles of 'inhalation by design'. A key feature of this work is the combination of balanced potency and pharmacodynamic duration with desirable pharmacokinetic and material properties, whilst keeping synthetic complexity to a minimum.

Inhalation by design: novel ultra-long-acting β(2)-adrenoreceptor agonists for inhaled once-daily treatment of asthma and chronic obstructive pulmonary disease that utilize a sulfonamide agonist headgroup.

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 sulfonamide agonist headgroup confers high levels of intrinsic crystallinity that could relate to the acidic sulfonamide motif supporting a zwitterionic form in the solid state.

SAR of a series of inhaled A(2A) agonists and comparison of inhaled pharmacokinetics in a preclinical model with clinical pharmacokinetic data.

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.

Inhaled muscarinic antagonists for COPD--does an anti-inflammatory mechanism really play a role?

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, tiotropium might also display anti-inflammatory properties.

A cell-based assay to assess the persistence of action of agonists acting at recombinant human beta(2) adrenoceptors.

Introduction: The aim was to establish a robust, 96-well, cell-based assay to assess the potency and persistence of action of agonists acting at human recombinant beta(2) adrenoceptors expressed in CHO (Chinese Hamster Ovary) cells and to compare this with published duration of action data in guinea pig isolated trachea and human bronchus.

Methods: Cells were treated with either: (i) beta-adrenoceptor agonist for 30 min, washed and cyclicAMP (cAMP) measured 30 min later-termed 'washed' cells or, (ii) treated with solvent for 30 min, washed, and then treated with beta-adrenoceptor agonist for 30 min and cAMP measured-termed 'unwashed' cells. The 'washed' EC(50) was divided by the 'unwashed' EC(50) to determine a rightward shift concentration ratio, which was indicative of the persistence of action at the receptor.

Inhaled adenosine A(2A) receptor agonists for the treatment of chronic obstructive pulmonary disease.

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.

Highly potent and selective zwitterionic agonists of the delta-opioid receptor. Part 1.

A series of zwitterionic delta-opioid agonists, with targeted physicochemistry, as a strategy to limit potential for CNS exposure, were prepared. These agents were found to possess exquisite potency and selectivity over mu and kappa-opiate activity. Furthermore, analogue 3a was found to display restricted CNS exposure, as evidenced by its inactivity in a rodent hyperlocomotion assay of central opiate activity.

PDE4 inhibition: a novel approach for the treatment of inflammatory bowel disease.

Inflammation is a hallmark of inflammatory bowel disease (IBD), and elevation of cAMP levels can inhibit the pro-inflammatory and tissue-destructive properties of leukocytes. Phosphodiesterase 4 (PDE4) is the predominant enzyme that metabolizes cAMP in inflammatory cells, and the anti-inflammatory and immunomodulatory potential of PDE4 inhibitors in human leukocytes, endothelium and epithelium is well documented. Although PDE4 inhibitors have been investigated as treatments for several inflammatory diseases, this has focused mainly on asthma and chronic obstructive disease (COPD).