Chronic pain is a global medical-health problem. It is estimated that approximately 20% of the adult population suffer from some form of chronic pain. Along with the physical and emotional burden that living with chronic pain brings to the individual, there is also a huge socio-economic cost implication currently estimated at more than €200 million per annum in Europe and at over $150 million in the USA. Unfortunately, because of a lack of efficacious treatments, chronic pain is poorly managed. Current therapies for chronic pain act upon well-established targets and have been shown not only to be inadequate for the majority of patients, with only 1 in 4 patients only finding up to 50% relief from their painful syndromes There is, therefore, a continued need for novel analgesic drugs that act at novel therapeutic targets. With the elucidation of the role of α1 glycine receptor (α1 GlyR) plays in nociceptive pathways it has become an attractive target for novel analgesic compounds. Previous work with the group has identified a series of potent bi-phenyl compounds targeting the α1 GlyR with EC50 values in the low nM range. However, these compounds suffered from poor physicochemical and pharmacokinetic properties. Work in this thesis describes the rational design and synthesis of a library of compounds which selectively target the α1 GlyR with EC50 values in the sub nano-molar range. We have successfully progressed from hit to lead stage with improved efficacy and DMPK properties. The lead compound has shown excellent PK profiles, CNS penetration properties and no toxicity issues. We have obtained proof-of concept for the lead compound in a rat model of neuropathic pain and are currently moving forward with lead optimisation.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:666716 |
| Date | January 2014 |
| Creators | Taylor, Lee |
| Publisher | University of Liverpool |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://livrepository.liverpool.ac.uk/2011359/ |
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