Valium without the sedation: Anxioselective GABAA receptor modulators for the treatment of anxiety disorders

This proposal aims to develop non-sedating anxiolytic drugs ("Valium without the sedation") that will represent the first major advance in the treatment of anxiety disorders for over 50 years. Anxiety disorders are the most common cause of patients visiting their GP and of these, generalized anxiety disorder (GAD) is the most prevalent. It affects around 5% of the population at some time in their life and is characterized by persistent, pervasive and excessive worrying. Consequently, it is a debilitating disorder that has an impact on society that is equivalent to depression and costs the UK in the region of £10 billion a year.
Current treatments for GAD are unsatisfactory for various reasons and there have been no major innovations since benzodiazepines were introduced in the early 1960s. Benzodiazepines are a class of so-called minor tranquilizer drugs the most famous of which is diazepam (Valium, aka "Mother's Little Helper"). Benzodiazepines are effective at reducing anxiety (i.e., they are anxiolytics) but sedation is a major side-effect. Until recently, all attempts to identify next-generation drugs that "dial-out" these side-effects, particularly the sedation, have been unsuccessful. However, following recent advances in our knowledge of how benzodiazepines work, we are now in a position to understand what is required to develop a non-sedating anxiolytic and, more importantly, how we can identify such drugs. It is these breakthroughs in our knowledge that this proposal aims to exploit.
Benzodiazepines act by altering the effects of a chemical in the brain (neurotransmitter) called gamma-aminobutyric acid (GABA). This neurotransmitter bind to four similar proteins in the brain called alpha1, alpha2, alpha3 and alpha5 GABAA receptors (GABAAR). Recent data suggests that the alpha1 subtype is responsible for sedation and consequently, it is hypothesised that by specifically affecting the alpha2 and alpha3 (the "anxiolytic") GABAAR subtypes while avoiding the alpha1 (the "sedation") subtype, it should be possible to identify an anxiolytic compound which is non-sedating. This hypothesis turns out to be correct with many experiments in animals showing that a GABAAR alpha2/alpha3 drug is indeed a non-sedating anxiolytic and early studies in man also support this hypothesis. Previous GABAAR alpha2/alpha3 drugs that were tested in man are no longer being developed due to a number of reasons unrelated to their mechanism of action and we therefore wish to continue with this area of research and develop novel GABAAR alpha2/alpha3 drugs that have the potential to revolutionise the treatment of anxiety disorders in general and GAD in particular.

This proposal seeks follow-on funding to identify and develop a novel non-sedating anxiolytic drug ready for testing in man. We will identify a single clinical candidate from a chemotype in which we are able to consistently identify molecules that are positive allosteric modulators (PAMs) at GABAA receptors containing either an alpha2 or alpha3 subunit (a2/a3-GABAAR; "anxiolytic" GABAARs) but which have minimal effects at the a1 subtype ("sedating" GABAARs). Based upon proprietary chemical starting points and structure-activity relationships originating from our AstraZeneca collaborators, we have significantly improved the pharmacology of these compounds to the point where we can demonstrate a non-sedating anxiolytic pharmacology in rodent species. We are now requesting funding to further fine tune our lead compounds and balance the current excellent pharmacological profile with emerging issues (such as solubility, CYP450 inhibition and PXR activation) in order to deliver the strongest possible clinical candidate. More specifically, we will identify 2-4 pre-candidate molecules from which a single candidate molecule will be selected to undergo full IND-enabling, GLP preclinical safety and toxicity testing. The outcome of this 33-month project will therefore be a drug ready for Phase 1 clinical studies. Subject to further clinical development, such a compound would be a first-in-class, non-sedating anxiolytic - "Valium without the sedation" - with the potential to transform the treatment of anxiety disorders, and more specifically generalised anxiety disorder (GAD), a debilitating and poorly-treated disorder with a lifetime prevalence of 5% and an estimated annual cost to the UK economy of around £10 billion.

The most obvious beneficiaries of the GABAAR a2/a3 PAMs originating from this project are the roughly 1-1.5 million people in the UK that suffer from generalised anxiety disorder (GAD) each year. This is a debilitating disorder producing a functional impairment on a par with major depression and although there are a number of drugs approved for treating GAD, these drugs have significant limitations. Hence, the selective serotonin and serotonin/noradrenaline reuptake inhibitors (SSRIs and SNRIs) and benzodiazepines have appreciable side effects and, in the case of SSRIs and SNRIs modest efficacy. These limitations result in large number of GAD patients being inadequately treated or avoiding treatment due to the side effects. Consequently, a novel, non-sedating anxiolytic drug has the potential to revolutionise the treatment of GAD and become the first-line treatment option.

Additional beneficiaries could include subjects with pain disorders or autism. For example, GABAAR a2/a3 PAMs have been shown to demonstrate efficacy in animal models of these disorders. Moreover, as the scientific community use published tool compounds and those coming from this project to further explore GABAAR-related physiology and pathophysiology, then so additional indications may become apparent once the sedation observed with benzodiazepines is dialled-out.