Quinolines as a novel structural class of potent and selective PDE4 inhibitors: Optimisation for oral administration

Woodrow, Michael D.; Ballantine, Stuart P.; Barker, Michael D.; Clarke, Beth J.; Dawson, John A.; Dean, Tony W.; Delves, C. J.; Evans, Brian; Gough, Sharon L.; Guntrip, Steven B.; Holman, Stuart; Holmes, Duncan S.; Kranz, Michael; Lindvaal, Mika K.; Lucas, Fiona; Neu, Margarete; Ranshaw, Lisa E.; Solanke, Yemisi; Somers, Don O.; Ward, Pamela; Wiseman, Joanne O.

doi:10.1016/j.bmcl.2009.01.045

Cited by 42 publications

(20 citation statements)

References 12 publications

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“…The similarities in marmoset and human PCLS could further be confirmed by analogous pIC 50 values (8.9 and 9.0, respectively) for the PDE4 inhibitor roflumilast. This is in line with previously shown pIC 50 values of 7.7 in human WBA [42]. In fact, we previously used human PCLS as a physiologically relevant acute inflammation model showing high homology to the in vivo situation [7].…”

Section: Discussionsupporting

confidence: 89%

LPS-Induced Lung Inflammation in Marmoset Monkeys – An Acute Model for Anti-Inflammatory Drug Testing

Seehase

Lauenstein

Schlumbohm³

et al. 2012

PLoS ONE

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Increasing incidence and substantial morbidity and mortality of respiratory diseases requires the development of new human-specific anti-inflammatory and disease-modifying therapeutics. Therefore, new predictive animal models that closely reflect human lung pathology are needed. In the current study, a tiered acute lipopolysaccharide (LPS)-induced inflammation model was established in marmoset monkeys (Callithrix jacchus) to reflect crucial features of inflammatory lung diseases. Firstly, in an ex vivo approach marmoset and, for the purposes of comparison, human precision-cut lung slices (PCLS) were stimulated with LPS in the presence or absence of the phosphodiesterase-4 (PDE4) inhibitor roflumilast. Pro-inflammatory cytokines including tumor necrosis factor-alpha (TNF-α) and macrophage inflammatory protein-1 beta (MIP-1β) were measured. The corticosteroid dexamethasone was used as treatment control. Secondly, in an in vivo approach marmosets were pre-treated with roflumilast or dexamethasone and unilaterally challenged with LPS. Ipsilateral bronchoalveolar lavage (BAL) was conducted 18 hours after LPS challenge. BAL fluid was processed and analyzed for neutrophils, TNF-α, and MIP-1β. TNF-α release in marmoset PCLS correlated significantly with human PCLS. Roflumilast treatment significantly reduced TNF-α secretion ex vivo in both species, with comparable half maximal inhibitory concentration (IC50). LPS instillation into marmoset lungs caused a profound inflammation as shown by neutrophilic influx and increased TNF-α and MIP-1β levels in BAL fluid. This inflammatory response was significantly suppressed by roflumilast and dexamethasone. The close similarity of marmoset and human lungs regarding LPS-induced inflammation and the significant anti-inflammatory effect of approved pharmaceuticals assess the suitability of marmoset monkeys to serve as a promising model for studying anti-inflammatory drugs.

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Section: Discussionsupporting

confidence: 89%

LPS-Induced Lung Inflammation in Marmoset Monkeys – An Acute Model for Anti-Inflammatory Drug Testing

Seehase

Lauenstein

Schlumbohm³

et al. 2012

PLoS ONE

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“…Future studies are needed to define dosing and treatment duration of ABR-215757. Moreover, ABR-215757 may have effects independent of S100A9 or S100A12, since recent work identified quinoline-3-carboxamides as potent inhibitors of phosphodiesterase 4, a cAMP metabolizing enzyme highly expressed in inflammatory and immune cells 27 , in addition to antioxidant activity and effect calcium channel activity 28 .…”

Section: Discussionmentioning

confidence: 99%

Beneficial effects of quinoline-3-carboxamide (ABR-215757) on atherosclerotic plaque morphology in S100A12 transgenic ApoE null mice

et al. 2013

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Objective There is an emerging widespread interest in the role of damage-associated molecular pattern molecules (DAMP) S100A8, S100A9 and S100A12 in cardiovascular and other diseases. In this study we tested the efficacy of ABR-215757, a S100 protein binding immuno-modulatory compound to stabilize atherosclerosis in transgenic ApoE null mice that express the human pro-inflammatory S100A12 protein within the smooth muscle cell (SM22α-S100A12). Methods Twelve-week old S100A12 transgenic/ApoE-/- and WT/ApoE-/- mice were treated with ABR-21575 for 5 weeks and were analyzed 4 month later. Results Surface plasmon resonance analysis demonstrated that S100A12 interacts with ABR-215757 in a zinc dependent manner in vitro. In vivo, ABR-215757 administration reduced features of advanced plaque morphology resulting in smaller necrotic cores, diminished intimal and medial vascular calcification, and reduced amount of infiltrating inflammatory cells. ABR-215757 normalized aortic expression of RAGE protein and normalized experimentally-induced delayed hypersensitivity. The effect of ABR-215757 was more prominent in ApoE-/- mice expressing S100A12 than in ApoE-/- animals lacking expression of human S100A12 protein. Conclusion Our data suggest that S100A12 is important for progression of atherosclerosis and can be targeted by the small molecule ABR-215757. The specific binding of quinoline-3-carboxamides to S100A12 attenuates S100A12-mediated features of accelerated murine atherosclerosis.

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“…Broad-spectrum antiinflammatory drugs, including inhibitors of the PDE4, p38 mitogenactivated protein kinase, nuclear factor-kappaB, and phosphoinositide-3-kinase-gamma, may be more effective [31]. The use of PDE4 inhibitors for the treatment of COPD is well documented in the scientific literature [7]. Zl-n-91 inhibited inflammatory cells infiltration in lungs of COPD-like rat model, improved lung function and decreased the level of COPD inflammation related cytokines.…”

Section: Discussionmentioning

confidence: 97%

“…Until now, the effective treatments for reducing the progression of COPD or for suppressing the inflammation of COPD are still not available [4]. However, accumulating preclinical and clinical evidence suggested that selective phosphodiesterase (PDE) 4 inhibitors are effective on inhibition of pulmonary inflammation and emphysema in COPD animal model and patients, respectively [5][6][7][8][9][10][11], thus, PDE4 inhibitors are of the most promising new anti-inflammatory agents for COPD remedy, and development of new generation of PDE4 inhibitors with less side-effects and more potent will light up the therapy of COPD.…”

Section: Introductionmentioning

confidence: 99%

Zl-n-91, a selective phosphodiesterase 4 inhibitor, suppresses inflammatory response in a COPD-like rat model

Wang

Jiang

Tang

et al. 2010

International Immunopharmacology

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Quinolines as a novel structural class of potent and selective PDE4 inhibitors: Optimisation for oral administration

Cited by 42 publications

References 12 publications

LPS-Induced Lung Inflammation in Marmoset Monkeys – An Acute Model for Anti-Inflammatory Drug Testing

LPS-Induced Lung Inflammation in Marmoset Monkeys – An Acute Model for Anti-Inflammatory Drug Testing

Beneficial effects of quinoline-3-carboxamide (ABR-215757) on atherosclerotic plaque morphology in S100A12 transgenic ApoE null mice

Zl-n-91, a selective phosphodiesterase 4 inhibitor, suppresses inflammatory response in a COPD-like rat model

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