Positive Allosteric Modulators (PAMS) of Strychnine-Sensitive Glycine Receptors - A New Concept in Treating Chronic Pain

The Problem/Background:

Our project addresses the longstanding urgent, unmet medical need of chronic pain. This debilitating condition affects about 20% of adults in Europe and in the USA, i.e. more than 8 million adult patients in the UK alone, wrecking individual lives and causing huge economical damage, predominantly in terms of lost working days. One key issue is the fact that the symptomatic medication currently available is effective only in about 40% of chronic pain sufferers and even these patients struggle to maintain the balance between adequate pain relief and their ability to cope with the substantive drug-induced adverse effects. This creates a vicious cycle of insufficient analgesia and unbearable side effects ultimately leading to discontinuation of treatment. Despite these problems growth in the neuropathic pain market alone is forecasted to rise to over $6.3 billion by 2017.

The Concept:

As regards understanding the pathophysiology of chronic pain there is evidence that loss of inhibitory neuronal transmission within the spinal cord plays a key role. This reduced capacity to inhibit nerve activity, comparable to defective dampers inside a piano, contributes to a functional dysequilibrium state of the central nervous system referred to as central pain sensitisation. The loss involves a particular type of cell membrane-spanning protein channels operated by distinct messenger molecules, mainly glycine. Thus, enhancement of glycinergic neurotransmission should compensate for this loss.

Our Proposal/Solution - A First-In-Kind Causal Treatment:

Consequently, we propose to develop a novel class of compounds which do enhance glycinergic neurotransmission effectively and selectively at the spinal cord level, thereby achieving the intended effect while avoiding unwanted and dangerous side effects, e.g. deep sedation/loss of consciousness. By the end of this project we should to be ready for development into a drug that will be taken orally for a limited period of time in order to reset the proper equilibrium state of the patient's central nervous system. Our ultimate aim is allowing chronic pain patients to regain a dramatically improved quality of life.

What has been achieved so far: We have successfully progressed to the discovery/synthesis of a novel class of compounds with selective enhancing effects at strychnine-sensitive glycine receptors, which do not mediate sedative effects. We are confident that this feature makes our development program highly competitive, viable and significant and have protected the Intellectual Property by filing a composition of matter patent. Moreover, we have obtained proof-of-concept for one key compound in a rat model of neuropathic pain.

Work Plan: The project is currently in the hit-to-lead stage development stage, i.e., we do already know that our concept works but we need to further improve chemistry features of our compounds in preparation for our ultimate aim, i.e. generating drugs which are safe/effective and can be taken orally, e.g. 3 times/day. We plan to achieve such optimised leads within two years.

Impact:

In view of the huge numbers of patients worldwide whose lives are wrecked by chronic pain, the fact that current treatment options are clearly insufficient and the dramatic toll on economies caused by millions of lost working hours, it is safe to say that our first-in-kind causal treatment option has the potential to have a dramatic beneficial impact on individuals and societies.

Our Solution Has Potential To Be A Platform-Technology:

We are confident, that our proposal can provide a platform technology addressing further medical conditions, e.g., opioid-withdrawal, alcoholism and anxiety.


Planned Route-to-Market/Exit Strategy:

Two pharmaceutical companies, Grunenthal and B.Braun have confirmed their desire to collaborate with our group, and each other, in the event of a successful completion of this programme.

Our project addresses the longstanding unmet need of chronic pain. This debilitating condition affects about 20% of adults in Europe and in the USA, one key issue being the fact that patients struggle to maintain the balance between adequate pain relief and their ability to cope with the substantive side effects caused by the symptomatic medication available. We have successfully progressed from target validation/hit identification to the discovery of a novel class of compounds with low nM positive allosteric modulating activity at alpha1 glycine receptors. Such an action compensates for the loss of inhibitory synaptic transmission within the dorsal horn of the spinal cord, which plays a key role in central pain sensitisation.
Here we propose to advance these early leads through lead development/optimisation to realise a quality lead molecule appropriate for further exploitation, aiming at a causal treatment for chronic pain.
Significant progress has been made so far funded by NESTech and the EPSRC/KTA leading to the filing of a composition of matter patent. For the first generation of compounds we have obtained successful proof-of-efficacy/selectivity in neuronal network models and proof-of-concept in vivo in a neuropathic pain rat model (intrathecal as well as oral administration). Moreover we have generated further hits while synthesising new optimised compounds.
As our main objective is an optimised lead series we will:
1) sequentially and systematically remove chemical liabilities
2) run SAR analysis and ligand-based design to create new analogues with improved potency, specificity and physico-chemical characteristics
3) evaluate the most promising leads with appropriate in vivo and ex vivo screens and derisk them by standard pharmacokinetic and toxicology experiments.
Two pharmaceutical companies, Grunenthal and B.Braun have confirmed their desire to collaborate with our group, and each other, in the event of a successful completion of this programme

Who will benefit


Patients (Worldwide)

Our project addresses the longstanding urgent, unmet medical need of chronic pain. This debilitating condition affects about 20% of adults in Europe and in the USA, i.e. more than 8 million patients in the UK alone, wrecking individual lives and causing huge economical damage, predominantly in terms of lost working days. One key issue is the fact that the symptomatic medication currently available is effective only in about 40% of chronic pain sufferers and even these patients struggle to maintain the balance between adequate pain relief and their ability to cope with the substantive drug-induced adverse effects. This creates a vicious cycle of insufficient analgesia and unbearable side effects ultimately leading to discontinuation of treatment.
Consequently, our project - by providing a first-in-kind causal treatment of chronic pain - will have a huge impact on patients' quality of life.


Commercial/Private Sector

Despite the current lack of efficient, reliable and tolerable treatment options for chronic pain growth in the neuropathic pain market alone is forecasted to rise to over $6.3 billion by 2017.

The industrial beneficiaries will be pharmaceutical companies with a focus on analgesics (in the context of this project we have engaged initially with Grunenthal and B.Braun).


Contribution to the Nation's Health/Wealth

In the best-case-scenario our proposed solution, which would provide a first-in-kind causal treatment, would dramatically reduce incidence and prevalence of chronic pain worldwide, thereby removing the cause for millions of lost working hours/year and vastly reducing the economic burden on societies.
Our solution has the potential to benefit about 8 million adult patients in the UK alone. As all these estimates refer exclusively to adult chronic pain patients it is safe to assume that the number of beneficiaries including e.g. adolescent chronic back pain patients will actually be even bigger.
Moreover, society, in particular the NHS will benefit from the trained personnel emerging from the programme equipped to contribute to UK industry in a high-tech sector. Longer term benefits will arise from the scientific advances enabling the development of new drugs for the treatment/prevention of chronic pain with associated health and environmental benefits which will give the UK economy a strong competitive edge in this field.

Individual Staff Working on the Project

The skills and contact network of the members of our research group, in particular, the project RAs will be strongly enhanced by close experiment/theory co-working in a cutting-edge translational science area, and engagement with pharmaceutical companies active in this field.