Biology Reference
In-Depth Information
inhibitors of PDE1 and PDE4 may work in concert to decrease proliferative
processes in airway smooth muscle cells, and so retard the remodeling process
while, at the same time, arrest inflammation (via PDE4 inhibition). Indeed, the
imidazonaphthyridine derivative (1; KF19514; Fig.
1
), which selectively inhibits
PDE1 and PDE4 with IC
50
values of 270 and 400 nM, respectively (Manabe et al.
1997
), was recently shown to suppress inflammation and airway remodeling in a
murine model of chronic asthma (Kita et al.
2009
), which provides further
evidence that PDE1 may play a role in regulating airway smooth muscle prolifer-
ation. In addition, extensive remodeling of the pulmonary vasculature is also
prevalent in COPD (see below and Chaouat et al.
2008
; Naeije and Barbera
2001
). Accordingly, if PDE1 also plays a central role in regulating the prolifera-
tion of pulmonary vascular myocytes, then inhibition of this enzyme could also
CH
3
CH
3
N
O
O
N
N
N
O
H
3
C
N
O
H
3
C
O
O
CH
3
N
H
3
C
N
N
O
N
CH
3
N
O
NH
CH
3
CH
3
O
NH
2
H
3
C
CH
3
1
(KF19514)
2
(RPL554)
3
(RPL565)
NO
2
H
3
C
N
CH
3
N
O
O
O
N
CH
3
O
2
N
HN
O
S
O
O
F
NH
H
3
C
H
3
C
N
S
O
H
3
C
N
N
H
NH
N
O
O
CH
3
OH
4
5
6 (YM-393059)
N
CH
3
N
CH
3
O
H
3
C
CH
3
7
Ibudilast
Fig. 1 Dual-selective and nonselective PDE inhibitors
