| Reference | 1. J Pharmacol Exp Ther. 2011 Apr;337(1):137-44. doi: 10.1124/jpet.110.173641. Epub
2011 Jan 4.
<br>
In vivo characterization of GSK256066, a high-affinity inhaled phosphodiesterase
4 inhibitor.
<br>
Nials AT(1), Tralau-Stewart CJ, Gascoigne MH, Ball DI, Ranshaw LE, Knowles RG.
<br>
Author information: <br>
(1)UK Discovery Biology, Respiratory Centre of Excellence for Drug Discovery,
GlaxoSmithKline Research and Development Ltd, Medicines Research Centre, Gunnels
Wood Road, Stevenage, Hertfordshire, United Kingdom SG1 2NY. [email protected]
<br>
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]a
mino}-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 < 0.05)
inhibition of LPS-induced pulmonary neutrophilia. The duration of action of
GSK256066 at 10 × ED(50) dose (10 μg/kg) was 12 h. GSK256066 and FP also
inhibited LPS-induced increases in exhaled nitric oxide (ED(50) 35 and 92 μg/kg,
respectively). In addition, GSK256066 inhibited pulmonary eosinophilia in rats
exposed to OVA (ED(50) 0.4 μg/kg). In ferrets, inhaled GSK256066 inhibited
LPS-induced pulmonary neutrophilia (ED(50) 18 μg/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.<br>
2. J Pharmacol Exp Ther. 2011 Apr;337(1):145-54. doi: 10.1124/jpet.110.173690. Epub
2011 Jan 4.
<br>
GSK256066, an exceptionally high-affinity and selective inhibitor of
phosphodiesterase 4 suitable for administration by inhalation: in vitro, kinetic,
and in vivo characterization.
<br>
Tralau-Stewart CJ(1), Williamson RA, Nials AT, Gascoigne M, Dawson J, Hart GJ,
Angell AD, Solanke YE, Lucas FS, Wiseman J, Ward P, Ranshaw LE, Knowles RG.
<br>
Author information: <br>
(1)Drug Discovery Institute, Faculty of Medicine, Imperial College London,
London, United Kingdom.
<br>
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-({3-[(dimethylamino)carbonyl]phenyl}sulfonyl)-8-methyl-4-{[3-methyloxy)
phenyl]amino}-3-quinolinecarboxamide (GSK256066), 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)
<0.5 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 α
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
(>380,000-fold versus PDE1, PDE2, PDE3, PDE5, and PDE6 and >2500-fold against
PDE7), inhibited PDE4 isoforms A-D with equal affinity, and had a substantial
high-affinity rolipram binding site ratio (>17). When administered
intratracheally to rats, GSK256066 inhibited LPS-induced pulmonary neutrophilia
with ED(50) values of 1.1 μg/kg (aqueous suspension) and 2.9 μg/kg (dry powder
formulation) and was more potent than an aqueous suspension of the corticosteroid
fluticasone propionate (ED(50) 9.3 μg/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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