Biology Reference
In-Depth Information
binding of CD36 to type 1 collagen, whilst other PDE3 inhibitors do not (Ikenoya
et al.
2007
).
5 Targeting PDEs for Treatment of IC in Future
Drug Development
Current pharmacotherapies for IC are limited and outcomes are far from optimal
with only modest relief of symptoms. None can reverse the progression of the
disease. In future drug development, PDE3 should still be considered a prime
target, as inhibition has a plethora of benefits on platelets and the vasculature.
However, the association of PDE3 inhibitors with unwanted cardiac effects and the
assumed class effect in heart failure patients (worsening of mortality) makes PDE3
inhibition a potential safety liability. Recent advances in studies on intracellular
compartmentalization of PDE isoforms in cardiac myocytes suggest that it is
possible to generate cAMP levels in local microdomains (Fischmeister et al.
2006
; Hambleton et al.
2005
; Movsesian
2002
). This characteristic may enable
separation of the inotropic effect of PDE3 inhibitors from the arrhythmogenic and
other detrimental effects on the heart. However, designing isoform-selective PDE
inhibitors has proven difficult (Thompson et al.
2007
) and identification of spatially
selective inhibitors (i.e., only inhibiting PDE3 in one compartment of the cell) is
likely to be even more challenging.
Synthetic analogues of prostacyclins such as beraprost and iloprost have been
evaluated on the basis of their ability to activate Gs and increase intracellular cAMP
in endothelium, platelets, and VSMCs. Some improvement in walking distance was
observed in small clinical studies (Lievre et al.
2000
; Muller-Buhl et al.
1987
), but
larger and two recent studies failed to confirm the effect on walking distance
(Creager et al.
2008
; Mohler et al.
2003b
).
Like cAMP, cGMP has also been a target for the treatment of IC, via the direct
activation of the soluble GC by the NO donor,
L
-arginine. However, the overall
benefits are largely negative (Boger et al.
1998
; Oka et al.
2005
; Wilson et al.
2007
).
Ataciguat (HMR-1766), a NO-independent, soluble GC activator, developed by
Sanofi-Aventis (Schindler et al.
2006
), was shown, in preclinical studies, to protect
coronary endothelium against ischemia/reperfusion (Kasseckert et al.
2009
) and
inhibit platelet activation (Schafer et al.
2006
). A clinical trial evaluated its effect
on patients with IC (ACCELA, clinicaltrials.gov). The trial results have not been
published, but in February 2009 development for this indication was terminated
without explanation (
https://www.thomson-pharma.com
). Another mechanism for
increasing intracellular cGMP is via inhibition of PDE5 as this enzyme is abundant
in VSMC and vascular endothelium, and has also been shown to be abundant in
platelets. In tissues thus far studied, PDE5 has the highest expression in the VSMCs
of the corpus cavernosum of the penis (Morelli et al.
2004
), allowing inhibitors to
be effective in the treatment of male erectile dysfunction. However, at this time,
PDE5 inhibitors have not been evaluated in IC.
