Biology Reference
In-Depth Information
The profile of an inhaled PDE4 inhibitor should comprise a long duration of
action in the lungs along with rapid systemic metabolism resulting in low systemic
exposure (AUC), high plasma protein binding, and low oral availability taking into
account that after inhalation a considerable part of the compound is swallowed,
altogether reducing the risk of systemic adverse events.
The benzamide AWD 12-281 (8, GSK842470, Elbion/GSK) was probably one
of the first potent (IC
50
at 3.5 nM) and selective PDE4 inhibitors specifically
designed for an inhaled development (Draheim et al.
2004
; Kuss et al.
2003
;
Gutke et al.
2005
). AWD 12-281 exhibits rather low solubility, high plasma protein
binding (
>
99%), and rapid clearance by phase II hepatic metabolism (apparently by
glucuronidation perhaps to the hydroxyl group attached to the indole moiety).
These properties may support extended lung retention, potentially fostering long
duration of action in the lungs, yet allowing low systemic exposure following
intratracheal administration as well as low oral bioavailability (Draheim et al.
2004
). In this context, AWD 12-281 retained the inhibition of ovalbumin (OVA)-
induced airway (bronchoalveolar lavage (BAL)) eosinophil influx in sensitized
Brown-Norway (BN) rats when given at the (suboptimal) dose of 30
m
gkg
1
intratracheally for up to 18 h before ovalbumin challenge, indicating a long duration
of action (Kuss et al.
2003
). In addition, AWD 12-281 administered intratracheally
to rats reduced OVA-induced BAL eosinophil influx with ED
50
of 7
m
gkg
1
i.t.
(BN rats) and LPS-induced BAL neutrophil influx with ED
50
of 0.02
m
gkg
1
i.t.
(Lewis rats) (Kuss et al.
2003
). At these dose levels, no relevant systemic exposure
occurs. In consequence, the observed suppressive effects of AWD 12-281 on the
lung inflammatory response to OVA or LPS are entirely attributed to the topical
actions of the PDE4 inhibitor confined to the lungs. Remarkably, no signs of emesis
or nausea from AWD 12-281 occurred in dogs following inhalation of up to
14 mg kg
1
per day over 4 weeks. Under these conditions, the systemic
C
max
was
1.5
m
M (Kuss et al.
2003
) that is close to the half-maximum inhibition of LPS-
induced TNF-
a
release in human whole blood (EC
50
of 900 nM, Kuss et al.
2003
)or
fMLP-induced neutrophil superoxide release in the presence of 80% autologous
human plasma. AWD 12-281 has been in clinical development for asthma and
COPD. Apparently results are not available in the public domain and further
development may have been terminated.
GSK256066 (9, GlaxoSmithKline) is a more recent topical PDE4 inhibitor in
clinical development for asthma, COPD, and allergic rhinitis. This quinoline
analogue achieves a strikingly high potency to inhibit PDE4 in the low pM range
(IC
50
at 3.2 pM) with no difference between the PDE4A-PDE4D subtypes
(Woodrow et al.
2009
; Knowles et al.
2009
). GSK256066 moderates early and
late airway response (reflected by a loss in FEV
1
) following allergen challenge in
steroid-naive atopic asthmatics after inhalation of 87.5
m
g per day, once daily for
7 days (Singh et al.
2010
). In this study, pharmacokinetic parameters were dis-
closed. Plasma area under the curve (AUC) at day 7 was only about 1.7-fold higher
compared to day 1, and
C
max
(35 pM) were comparable. Given an extrapolated
C
max
unbound to proteins of 0.6 pM (plasma protein binding of 98.2%) and half-
maximum inhibition of LPS-induced TNF-
a
release in human whole blood at
