Searching for relief
Fine Chemicals Group: Research into effective relief from pain is
thriving and the
outlook for pain sufferers is promising, as a November 2006 conference, Nociception, showed
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| Pain is likely to affect all of us at some time in our lives. The need for advanced therapies was discussed at an SCI meeting in November 2006. |
Pain is
an indiscriminate affliction. It is likely to affect everyone, probably directly, if not indirectly,
during his or her lifetime. Current therapies are not
sufficient to satisfy the needs of patients suffering from
pain. Even one of the best options available, gabapentin,
provides only 50% pain relief for approximately one fifth
of the patient population to which it is prescribed. Clearly,
there is an urgent medical need for new highly effective
therapies that do not come with the undesirable baggage
of side effects. ‘Nociception: taking the pain out of drug
discovery’ was a one day symposium organised by the SCI
fine chemicals group that took place at SCI headquarters
in Belgrave Square, London, in November 2006 to assess the
status of this therapeutic area and to provide insights into
possible future therapies from ongoing drug discovery
research programmes.
| He criticised some of the existing preclinical models for their inability to replicate what patients experience in the clinic |
Andrew Rice (Imperial College) initiated proceedings
with a provocative review of the area of neuropathic
pain. He described, often in graphic detail, diseases associated
with neuropathic pain, for example, traumatic
nerve injury, and he criticised some of the existing preclinical
models for their inability to replicate what patients
experience in the clinic, despite being widely used
in neuropathic pain research programmes. However, he
was quick to highlight that new options for pre-clinical
models being developed are directed towards representing
the types of pain patients experience and the types
of symptoms measured in clinical trials.
Gerard Giblin (GlaxoSmithKline) detailed the search
for cannabinoid (CB) receptor 2 agonists for the treatment
of inflammatory pain including the discovery and
optimisation of highly potent compounds with exquisite
selectivity over the other well characterised CB receptor
(CB1). Efficacy was demonstrated in pre-clinical models
and this resulted in the selection of the first clinical
candidate, GW842166X. J Guy Breitenbucher (Johnson
& Johnson) gave a presentation on the identification of
fatty acid amide hydrolase (FAAH) inhibitors. FAAH has
a key role in the endocannabinoid pathway because it
is responsible for the breakdown of a natural ligand for
CB1 and CB2, anandamide. By blocking the action of
FAAH, efficacy in models of analgesia was achieved.
Martin Gunthorpe (GlaxoSmithKline) discussed the
discovery of novel antagonists for the transient receptor
potential vanilloid 1 (TRPV1) ion channel. This receptor
is activated by both chemical and physical stimuli and
is implicated in neuropathic and inflammatory pain.
The extensive but ultimately successful journey to a
clinical candidate was disclosed and Phase II trials are
in progress. Karl Gibson (Pfizer) focused on allosteric
antagonists of the metabotropic glutamate receptor
sub-type 1 (mGluR1). A careful medicinal chemistry approach
was described to design compounds with excellent
potency, selectivity and suitable pharmacokinetic
properties. But compounds interacting selectively on
mGluR1 were shown to induce unexpected toxicity,
precluding their advancement into the clinic and completes
the picture for mGluR1 antagonists, which until
recently was a popular research target for pain.
Drugs targeting the α2δ sub-unit of voltage-gated
calcium channels are already in the market place including
gabapentin and pregabalin, but they do not necessarily
meet the needs of the patient population they
serve. David Rawson (Pfizer) presented research efforts
towards the next generation of α2δ ligands for neuropathic
pain. In the final presentation, Dean Wilson
(Vertex) covered ion channel modulators. Historically,
this has been a very challenging area of research but,
through proprietary technology, Vertex has identified
good leads for sub-type selective modulators of voltagegated
sodium channels. The optimisation of these leads
has provided compounds that have been tested in pharmacology
studies demonstrating encouraging efficacy
and safety profiles.
Stephen East,
Evotec (UK)
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