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

Lead Research Organisation: University of Liverpool
Department Name: Institute of Translational Medicine

Abstract

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.

Technical Summary

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

Planned Impact

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.

Publications

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Description PAMS 
Organisation Eberhard Karls University of Tubingen
Department Experimental Anaesthesiology
Country Germany 
Sector Academic/University 
PI Contribution Invention/synthesis of compounds for prevention/treatment of central pain sensitisation
Collaborator Contribution Efficacy/selectivity in neuronal network models
Impact N/A
Start Year 2013
 
Description PAMS 
Organisation King's College London
Department Pain and Neurorestoration
Country United Kingdom 
Sector Academic/University 
PI Contribution Invention/synthesis of compounds for prevention/treatment of central pain sensitisation
Collaborator Contribution In-vivo proof-of-concept experiments
Impact Preliminary proof-of-concept
Start Year 2013
 
Description PAMS 
Organisation Technical University of Darmstadt
Department Neurophysiology
Country Germany 
Sector Academic/University 
PI Contribution Invention/synthesis of compounds for prevention/treatment of central pain sensitisation
Collaborator Contribution In-vitro efficacy/selectivity
Impact Confirmation of hits
Start Year 2012
 
Title Analgesia 
Description Protection of a novel class of positive allosteric modulators of strychnine-sensitive glycine receptors aiming at prevention/treatment of chronic pain 
IP Reference AWE/P210534GB 
Protection Patent application published
Year Protection Granted 2015
Licensed No
Impact We are currently in negotiations with potential investors.
 
Title Pharmacologically Active Compounds 
Description 'Composition-of-matter' protection for PAMS (morpholino-derivatives of di-isopropylphenol), a first-in-class family of compounds aiming at preventing/treating chronic pain 
IP Reference EP3087055 
Protection Patent granted
Year Protection Granted 2018
Licensed No
Impact 'Composition-of-matter' protection for PAMS (morpholino-derivatives of di-isopropylphenol), leading to a collaboration contract with NIH/NINDS with regard to investigating PAMS' potential as anti-epileptic drugs
 
Title Pharmacologically Active Compounds 
Description 'Composition-of-matter' protection for PAMS (positive allosteric modulators of strychnine-sensitive glycine receptors) ), a first-in-class family of compounds (morpholino-derivatives of di-isopropylphenol) aiming at preventing/treating chronic pain. 
IP Reference US9676786 
Protection Patent granted
Year Protection Granted 2017
Licensed No
Impact Led to a collaboration contract with NIH/NINDS on investigating PAMS' potential as novel anti-epileptic drugs (2018)
 
Title Pharmacologically Active Compounds 
Description 'Composition-of-matter' protection for PAMS (positive allosteric modulators of strychnine-sensitive glycine receptors) ), a first-in-class family of compounds (morpholino-derivatives of di-isopropylphenol) aiming at preventing/treating chronic pain. 
IP Reference US9676786 
Protection Patent granted
Year Protection Granted 2018
Licensed No
Impact Led to a collaboration contract with NIH/NINDS on investigating PAMS' potential as novel anti-epileptic drugs (2018)
 
Title Propofol Derivatives 
Description Novel class of positive allosteric modulators of strychnine-sensitive glycine receptors for prevention/treatment of chronic pain 
IP Reference US9676786 
Protection Patent application published
Year Protection Granted 2015
Licensed No
Impact The project has raised interest from pharma companies. Negotiations are ongoing.
 
Description Involving RCoA/NIAA/Patient Representatives 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Type Of Presentation Paper Presentation
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact Discussion with the Research Council of the NIAA involving patient representatives leading to a formal letter of support attached to the MRC DPFS full application

Formal letter of support submitted with the full application to MRC DPFS
Year(s) Of Engagement Activity 2012
 
Description Symposium 'Molecular Mechanisms of Anaesthesia', MAC 2015, Bonn, Germany 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited organisation of a Symposium ('Transmitter-gated CNS chloride channels - New targets for emerging drugs combating chronic pain').
About 250 international researchers attended. The presentations were well received and sparked a prolific debate leading to new collaborations.
Year(s) Of Engagement Activity 2015