http://www.future-science.com/doi/pdf/10.4155/ppa.12.5
(je ne vous colle pas les mol et le reste voir le doc)
A combination of Ang II receptor blockade with
NO-donating activity may be effective in treating resistant
hypertension in patients with elevated SBP, primarily
the elderly [23,24]. These patients have impaired
endothelial
function, resulting in diminished formation
of NO. ARBs have been shown to improve endothelium
function and increase endogenous NO formation.
ARB/NO donors have been disclosed by three companies,
two of which (Merck and NicOx) were joint
assignees on many applications as part of a research collaboration.
ARB/NO donors from Merck and NicOx
were derived by linking ARBs with NO-releasing
moieties via ester groups or other ‘soft’ functionalities
(Figure 6; compounds 7 and
[108,109]. These ARB/NO
donors are prodrugs that must undergo metabolism
(mostly ester hydrolysis) to liberate the pharmacologically
active ARB species. Compound 8 with two nitrooxy
groups was shown to decrease SBP in the conscious
spontaneously hypertensive rat (SHR) over a 24-h period,
in contrast to compounds such as 9 with only a single
nitrooxy group, which did not show significant blood
pressure-lowering activity in the SHR at the 24-h time
point. NicOx has patented a series of ARB/NO donors
such as 10, which are claimed to be long-acting agents,
with potent in vitro activity in isolated rabbit thoracic
preparations and extended pharmacological activity in
the SHR [110]. NitroMed
has identified a series of valsartan
analogs with nitrooxy groups such as 11, which
exhibit potent affinity in an Ang II receptor-binding assay
(Figure 7) [111]. Merck has also investigated a series of
diazeniumdiolates such as 12, which can be metabolized
in vivo to give an ARB and an intermediate
capable of releasing two
molecules of NO under physiological
conditions [112]. The formation
of NO from diazeniumdiolates has
been recently reviewed [25].
The ARB/NO donors are part
of a broader class of NO pathway
modulators that saw considerable
patent activity between 2007 and
2011, including endothelial NO
synthase upregulators, PDE5 inhibitors,
sGC activators and a variety
of other NO-donating agents
(Figure 8 & Supplementary Table 2).
Summaries of the pharmacology
underlying the different drug
classes in the NO pathway and a
description of the role of NO as a
vasodilating agent are provided in
the section ‘NO pathway modulators’.
Non-NO donor modulators
of this pathway may address one
of the shortcomings associated
with nitrate (NO-donating) monotherapy
(i.e., the development of
tolerance) that has prevented more
widespread use of the therapy.
In the NO pathway, four drug
classes attracted the most interest,
including sGC activators, PDE5
inhibitors, ARB/NO donors and
endothelial NO synthase upregulators,
with patent counts of 22,
18, 13 and eight applications, respectively.
Novel diuretic agents
and PDE3 inhibitors with NOdonating
capacity were also disclosed,
although the patent counts
were low.