Quinolines as a novel structural class of potent and selective PDE4 inhibitors. Optimisation for inhaled 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.2009.04.012

Cited by 47 publications

(26 citation statements)

References 9 publications

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“…1) as a free base (Woodrow et al, 2009) and in micronized form for in vivo studies, roflumilast, N-(3,5-dichloropyrid-4-yl)-(1-(4-fluorobenzyl)-5-hydroxy-indole-3-yl)glyoxylic acid amide tofimilast,4,6,7, , and streptavidin/biotinylated anti-TNF␣ antibody mix and rutheniumtagged anti-TNF␣ monoclonal antibody were from IGEN International Inc. (Gaithersburg, MD). Lipopolysaccharide (LPS), cAMP, bovine serum albumin (BSA), EGTA, and magnesium chloride solution were from Sigma-Aldrich Company Ltd. (Gillingham, Dorset, UK).…”

Section: Methodsmentioning

confidence: 99%

“…Consequently, we sought to identify potent antiinflammatory PDE4 inhibitors that would have minimal systemic impact when administered by the inhaled route, reasoning that such a compound could show an improved therapeutic index and so be dosed to higher levels of both PDE4 inhibition and anti-inflammatory efficacy than is possible with oral PDE4 inhibitors. In this article, we describe the in vitro pharmacology and preliminary in vivo characterization of a novel tight binding inhibitor of PDE4, 6-({3-[(dimethylamino)carbonyl]phenyl}sulfonyl)-8-methyl-4-{[3-methyloxy)phenyl]amino}-3-quinolinecarboxamide (GSK256066), which was derived from this rational design-based medicinal chemistry effort (Woodrow et al, 2009) and has been undergoing clinical trials for asthma and COPD. Studies described include enzyme kinetics, in vitro potency and selectivity, cellular and whole blood activity, and in vivo antiinflammatory activity in a rat acute lung inflammation model.…”

Section: Introductionmentioning

confidence: 99%

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GSK256066, an Exceptionally High-Affinity and Selective Inhibitor of Phosphodiesterase 4 Suitable for Administration by Inhalation: In Vitro, Kinetic, and In Vivo Characterization

Tralau-Stewart¹,

Williamson²,

Nials³

et al. 2011

J Pharmacol Exp Ther

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Oral phosphodiesterase (PDE) 4 inhibitors such as roflumilast have established the potential of PDE4 inhibition for the treatment of respiratory diseases. However, PDE4 inhibitor efficacy is limited by mechanism-related side effects such as emesis and nausea. Delivering the inhibitor by the inhaled route may improve therapeutic index, and we describe 6-, an exceptionally high-affinity inhibitor of PDE4 designed for inhaled administration. GSK256066 is a slow and tight binding inhibitor of PDE4B (apparent IC 50 3.2 pM; steady-state IC 50 Ͻ0.5 pM), which is more potent than any previously documented compound, for example, roflumilast (IC 50 390 pM), tofimilast (IC 50 1.6 nM), and cilomilast (IC 50 74 nM). Consistent with this, GSK256066 inhibited tumor necrosis factor ␣ production by lipopolysaccharide (LPS)-stimulated human peripheral blood monocytes with 0.01 nM IC 50 (compared with IC 50 values of 5, 22, and 389 nM for roflumilast, tofimilast, and cilomilast, respectively) and by LPS-stimulated whole blood with 126 pM IC 50 . GSK256066 was highly selective for PDE4 (Ͼ380,000-fold versus PDE1, PDE2, PDE3, PDE5, and PDE6 and Ͼ2500-fold against PDE7), inhibited PDE4 isoforms A-D with equal affinity, and had a substantial high-affinity rolipram binding site ratio (Ͼ17). When administered intratracheally to rats, GSK256066 inhibited LPS-induced pulmonary neutrophilia with ED 50 values of 1.1 g/kg (aqueous suspension) and 2.9 g/kg (dry powder formulation) and was more potent than an aqueous suspension of the corticosteroid fluticasone propionate (ED 50 9.3 g/kg). Thus, GSK256066 has been demonstrated to have exceptional potency in vitro and in vivo and is being clinically investigated as a treatment for chronic obstructive pulmonary disease.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

GSK256066, an Exceptionally High-Affinity and Selective Inhibitor of Phosphodiesterase 4 Suitable for Administration by Inhalation: In Vitro, Kinetic, and In Vivo Characterization

Tralau-Stewart¹,

Williamson²,

Nials³

et al. 2011

J Pharmacol Exp Ther

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“…19 This identified the dimethylcarboxamide as a solvent exposed moiety that we hypothesized could support the attachment of a chemical linker. We reasoned the use of a noncleavable linker would provide in vivo stability of the conjugate and correspondingly improve the specificity of drug delivery.…”

Section: Human Anti-cd11a-pde4 Inhibitor Adc Generationmentioning

confidence: 97%

Targeted Delivery of an Anti-inflammatory PDE4 Inhibitor to Immune Cells via an Antibody–drug Conjugate

Pearson

Lim

et al. 2016

Molecular Therapy

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SIGNIFICANCEPDE4 inhibitors are clinically validated molecules with considerable efficacy but relatively low safety profile in treating chronic inflammatory diseases. Therefore, the potential expansion of clinical indications of these molecules is relatively unexplored.Bringing to bear medicinal chemistry and bio-conjugation methods, we generated αhuCD11a-PDE4 and its mouse equivalent αmuCD11a-PDE4, which target the pan-immune cell surface antigen CD11a and demonstrated potent in vitro suppression of inflammation that is explicitly receptor-dependent. Pharmacokinetic and pharmacodynamic analysis of αmuCD11a in vivo revealed translation of these effects. With antibody-based therapies becoming a mainstay in the treatment of inflammation, this study provides critical validation for a new paradigm which could lead to second generation PDE4 inhibitors with an improved safety and efficacy.

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“…6-({3-[(Dimethylamino)carbonyl]phenyl}sulfonyl)-8-methyl-4-{[3-methyloxy)phenyl]amino}-3-quinolinecarboxamide (GSK256066), is a novel, selective PDE4 inhibitor designed to be administered by the inhaled route for the treatment of inflammatory lung diseases (Woodrow et al, 2009). The preliminary pharmacology of GSK256066 has been described (Knowles et al, 2009b;Tralau-Stewart et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

In Vivo Characterization of GSK256066, a High-Affinity Inhaled Phosphodiesterase 4 Inhibitor

Nials¹,

Tralau-Stewart²,

Gascoigne³

et al. 2011

J Pharmacol Exp Ther

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Oral phosphodiesterase (PDE) 4 inhibitors have demonstrated clinical efficacy in chronic obstructive pulmonary disease and asthma. Preclinical and clinical investigation of inhaled PDE4 inhibitors is ongoing. 6-({3-[(Dimethylamino)carbonyl]phenyl}-sulfonyl)-8-methyl-4-{[3-methyloxy)phenyl]amino}-3-quinolinecarboxamide (GSK256066) is an exceptionally high-affinity and selective inhibitor of PDE4 designed for inhaled delivery. The aim of these studies was to investigate the potency, duration of action, and therapeutic index of GSK256066 in animal models of pulmonary inflammation. The effects of intratracheally administered GSK256066 were investigated in rat lipopolysaccharide (LPS)-and ovalbumin (OVA)-induced models of acute pulmonary inflammation. In some studies, fluticasone propionate (FP) was included as a comparator. The therapeutic index (anti-inflammatory effect versus emesis) of GSK256066 was studied in ferrets where acute pulmonary inflammation was induced with inhaled LPS. In rats, GSK256066 and FP caused significant (p Ͻ 0.05) inhibition of LPS-induced pulmonary neutrophilia. The duration of action of GSK256066 at 10 ϫ ED 50 dose (10 g/kg) was 12 h. GSK256066 and FP also inhibited LPS-induced increases in exhaled nitric oxide (ED 50 35 and 92 g/kg, respectively). In addition, GSK256066 inhibited pulmonary eosinophilia in rats exposed to OVA (ED 50 0.4 g/kg). In ferrets, inhaled GSK256066 inhibited LPS-induced pulmonary neutrophilia (ED 50 18 g/kg), and no emetic episodes were observed. Thus, GSK256066 may have an improved therapeutic index compared with oral PDE4 inhibitors, e.g., cilomilast and roflumilast. In summary, GSK256066 demonstrates potent and long-lasting anti-inflammatory effects in animal models of pulmonary inflammation and does not induce emetic episodes in ferrets. GSK256066 has potential as an inhaled therapeutic for the treatment of asthma and chronic obstructive pulmonary disease.

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Quinolines as a novel structural class of potent and selective PDE4 inhibitors. Optimisation for inhaled administration

Cited by 47 publications

References 9 publications

GSK256066, an Exceptionally High-Affinity and Selective Inhibitor of Phosphodiesterase 4 Suitable for Administration by Inhalation: In Vitro, Kinetic, and In Vivo Characterization

GSK256066, an Exceptionally High-Affinity and Selective Inhibitor of Phosphodiesterase 4 Suitable for Administration by Inhalation: In Vitro, Kinetic, and In Vivo Characterization

Targeted Delivery of an Anti-inflammatory PDE4 Inhibitor to Immune Cells via an Antibody–drug Conjugate

In Vivo Characterization of GSK256066, a High-Affinity Inhaled Phosphodiesterase 4 Inhibitor

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