Biology Reference
In-Depth Information
clinical efficacy due to potential cardiovascular toxicity (see below). Nevertheless,
in September 2009, Verona Pharma announced that trials of 2 had been successfully
completed. According to the company's website, the compound has a “
good safety
profile and had beneficial effects in terms of bronchodilation and bronchoprotec-
tion in asthmatics and a reduction in the numbers of inflammatory cells in the nasal
passages of allergic rhinitis patients
” (see
http:/www.veronapharma.com/s/Lead
DrugRPL554.asp
). Compound 3 (RPL 565; Fig.
1
) lacks the urea side chain of
2 and has an ether link to a dipropan-2-ylbenzene moiety. Unlike 2, this derivative
inhibits PDE3 and PDE4 with similar potencies (IC
50
¼
107 nM and 1.2
m
M,
respectively) (Boswell-Smith et al.
2006
). Although it might be expected that
3 would be the desired development candidate because of its ability to inhibit
PDE3 and PDE4 in vivo and so maximize the chances of synergy, no clinical
data have been reported.
Several other companies including Nycomed, Kyorin, and the Leiden/Amster-
dam Centre for Drug Research have patents protecting dual PDE3/PDE4 inhibitors
of varied structural classes. Interested readers should consult Pages et al. (
2009
) for
details.
While the scientific rationale is clear for inhibiting, simultaneously, both PDE3
and PDE4 (see above), there may be major safety issues with this approach.
Specifically, concerns about cardiovascular toxicity may explain why there are
relatively few patents claiming dual-selective compounds for respiratory diseases
when compared to highly selective inhibitors of PDE4. Historically, PDE3 inhibi-
tors were developed as “safer” alternatives to cardiac glycosides for the treatment
of dilated cardiomyopathy. Although this objective was realized in acute dosing
studies with notable beneficial effects on myocardial contractility and on vascular
smooth muscle tone, chronic treatment resulted, paradoxically, in a significant
increase in mortality (Amsallem et al.
2005
; Movsesian
2003
). These findings are
of concern as some individuals who suffer with COPD also have right heart failure
secondary to PH (Naeije
2003
). Thus, a PDE3/PDE4 inhibitor would, presumably,
be contraindicated in this clinical setting. Moreover, the long-term effect of this
type of drug in individuals with mild COPD and normal lung function is unknown.
Another potential cause for concern is arteritis, which is believed to be due to
changes in hemodynamics produced by prolonged vasodilation of various vascular
beds. There is an extensive literature on PDE3 inhibitor-induced arteriopathy in
laboratory animals with the splanchnic vessels and coronary arteries of rats and
dogs, respectively, being the most susceptible to lesions (Joseph
2000
). Whether
arteriopathies evoked by PDE3/PDE4 inhibitors are to be expected in humans with
chronic
use, as would be required in COPD, is unknown. However, the nonselective
PDE inhibitors theophylline, pentoxifylline, and ibudilast, and the selective PDE3
inhibitor, cilostamide, have been used clinically for many years with no evidence,
to date, of vascular toxicity.
If PDE3/PDE4 inhibitors are to be an effective treatment option, a clinically
meaningful bronchodilator response would be required without coincident changes
in cardiac function and systemic blood pressure (Brunnee et al.
1992
; Wilsmhurst
and Webb-Peploe
1983
; Yamashita et al.
1990
). The fact
that pumafentrine
