Biology Reference
In-Depth Information
to curb hyperactive structural cells may potentially alleviate these extrapulmonary
manifestations. This hypothesis should be challenged in future investigations.
The history of PDE4 inhibitors dates back at least three decades and perhaps
the first clinical proof-of-concept study was with Ro 20-1724 that was later char-
acterized as a PDE4 inhibitor. This compound reduced plaque size in psoriasis
patients when administered topically as reported by Stawiski and colleagues in
1979 (Stawiski et al.
1979
). Immediately following the discovery of PDE4 in the
1980s, there was an exponential interest in PDE4 inhibitors. This was particularly
attributed to the excellent drugability of PDE4 as a target and the rapidly accumu-
lating evidence on the potential of PDE4 inhibitors to mitigate inflammation.
However, first-generation PDE4 inhibitors comprising Ro 20-1724, rolipram, or
denbufylline were associated with side effects such as nausea and vomiting that
prevented their clinical development. More recent developments, including cilomilast,
roflumilast, and apremilast (Fig.
1
), were specifically designed to temper this adverse
profile and have been investigated in large clinical trials, mostly in COPD or asthma,
or with apremilast in psoriasis.
The wealth of knowledge on the biology of PDE4, medicinal chemistry of
selective PDE4 inhibitors, and the abundance of cellular and animal effects asso-
ciated with PDE4 inhibitors have been exhaustively summarized and discussed in
excellent and authoritative recent reviews (Bender and Beavo
2006
; Conti and
Beavo
2007
; Boswell-Smith and Spina
2007
; Spina
2008
; Pag`s et al.
2009
; Press
and Banner
2009
). This chapter, however, is an attempt to collate our current
knowledge and opinion on the clinical pharmacokinetics of PDE4 inhibitors and
to discuss, where possible, how pharmacokinetic profiles might modify clinical
O
CH
3
3
N
NH
N
CH
3
2
H
O
1
O
H
3
C
CH
3
NH
O
CH
3
H
3
C
O
S
O
5
CH
3
O
4
O
O
O
O
O
O
HN
OH
CI
F
N
F
CI
F
HN
F
N
O
7
O
CI
O
6
Fig. 1 Chemical structures of selected oral PDE4 inhibitors, which have been in clinical devel-
opment. (1) rolipram; (2) ibudilast; (3) tetomilast; (4) cilomilast; (5) oglemilast, (6) roflumilast, (7)
apremilast
