Thursday, December 13, 2012
Boston team tested GlaxoSmithKline plc's transient receptor potential vanilloid 4 (TRPV4; VRL2) inhibitor GSK2193874 in a lung-on-a
chip model, the pharma reported on the discovery and subsequent animal studies
of the edema therapeutic.
known to mediate Ca2+ flux across the plasma membrane and promote vascular
relaxation when activated by mechanical activities such as enhanced pressure.5,6
studies, including work at the University of South Alabama, showed that
knocking out Trpv4 in mice prevented increased vessel permeability and
pressure-induced pulmonary edema.7 Now, the group from South Alabama
has teamed up with GSK to develop a TRPV4 inhibitor.
In a paper
published in Science Translational Medicine,3 Kevin Thorneloe and
colleagues used small molecule screening and chemical optimization to develop
GSK2193874. Thorneloe is a senior scientific investigator at GSK.
isolated mouse and rat lungs, GSK2193874 reversed pulmonary edema. The
therapeutic had no effect on the lungs at low pressure, suggesting it acts
specifically against pressure-induced vessel leakage.
also normalized pressure and decreased pulmonary edema compared with vehicle
control in mouse models of chronic and acute venous pressure elevation. In the
chronic model, GSK2193874 given one week after myocardial infarction-induced
increases in pressure reversed pulmonary edema.
is still a discovery effort. Safety and toxicology studies are the next steps,"
is expressed in most cells in the body. This is a potential problem for
inhibitors, and they may therefore be doing things that you don't want them to
do, but the authors of the paper did a good job addressing some of the potential
problems," said Wolfgang Kübler, associate professor of surgery and
physiology at the University of Toronto. "For example,
they showed that heart rate, blood pressure and kidney function were not affected
by the inhibitors. They also showed that the effects of diuretics, which you
would still want to give patients, were not altered."
He added, "This
proves that if you block the TRPV4 channel, you can inhibit the further effects
on fluid leakage. It also may support another pathological mechanism for TRPV4
that we have found. TRPV4 may also stimulate a cascade that inhibits the removal
of fluid from the air spaces, so inhibiting the channel may both prevent
leakage and increase fluid removal, but the team would need to confirm the
relevance of this mechanism."
said GSK has filed for patents covering GSK2193874. -LM