Abbott's H3 histamine receptor antagonist, ABT-239, represents a promising agent for the treatment of a variety of CNS disorders. Primarily this candidate appears to be of potential use in the treatment of cognitive components of ADHD, Alzheimer's and schizophrenia. Cognitive impairment is an important yet unmet component of schizophrenia, and the promise of ABT-239 in the treatment of this disease is even greater given its ability to, in addition, improve measure of positive symptomology associated with schizophrenia.

Stored in mast cells and peripheral neurones, histamine release has been implicated in the pathogenesis of various inflammatory reactions and also abnormal gastric acid secretion; H1 and H2 histamine receptor antagonists have been developed for these conditions. Histaminergic neurons are also located in the tuberomammillary nucleus of the posterior hypothalamus and project their axons into brain regions including the hypothalamus, thalamus, cerebral cortex, amygdala, and septum. Histamine H3 receptors, which are predominantly expressed in the CNS, act as autoreceptors in presynaptic neurons, and control histamine turnover. Histamine H3 antagonists were first investigated as possible modulators of food intake however it is now clear that histamine H3 receptors are involved in arousal disorders (eg attention deficit hyperactivity disorder - ADHD) and conditions associated with reduced cognition (eg Alzheimer's disease). Both of these conditions are fully evaluated in our recent feature "CNS Drug Discoveries: What the future holds" [access this report].

In 2000, it was estimated that 4-5 million individuals (mainly children) were diagnosed with ADHD. Over 8 million adults in the US may exhibit the symptoms of ADHD, although only an estimated 600,000 are being treated. The value of the ADHD market was US$1.7 billion in 2003 and it is now the 11th largest and one of the fastest growing segments of the CNS market by sales. Global sales of ADHD are forecast to reach US$3 billion by 2010. This will be due to greater diagnosis and penetration in the treatment of new patients particularly adult ADHD, improvements in patient compliance due to the launch of new formulations, new non-schedule II drugs and the development of novel classes of drugs in late-stage clinical trials. The vast majority of ADHD patients are treated with psychostimulants.

The identification of H3 receptor antagonists has received considerable attention in the field of attention and cognitive disorders since first generation antagonists were shown to promote attention and wakefulness and improve short-term and social memory in rodents. Movement of candidates into clinical phase development has however been slow. First generation antagonists suffered poor selectivity, complex pharmacology and potential interactions with cytochrome P450 enzymes. The identification of newer molecules has met various pharmacological hurdles including the presence of multiple and biologically distinct splice isoforms and also inter-species difference.

Progress has however been made in the development of H3 receptor antagonists, notably by researchers at Abbott. A-304121, A-317920 and A-349821 have demonstrated efficacy in animal models, although species differences in receptor binding, poor blood brain barrier penetration and the potential cardiovascular adverse effects have blocked their progress. A new Abbott molecule, ABT-239, looks to be more promising. Esbenshade et al (2005) have reported that this molecule has high affinity and selectivity for human H3 receptors, good oral bioavailability and excellent blood brain barrier penetration. In a second paper Fox et al (2005) report the activity of ABT-239 in various rodent models.

Using a pharmacological model used to demonstrate in vivo potency Fox et al determined the minimal active dose of ip ABT-239 as 0.1mg/kg. Similar potency was reported in a model of ADHD learning defects. One component of cognition that is impaired in Alzheimer's disease is spatial memory is and ABT-239 also demonstrated efficacy in a model of this component of cognition. A third type of memory, social memory is, like spatial memory, impaired in Alzheimer's disease and ABT-239 was a particularly potent stimulator of social memory. ABT-239 is therefore a candidate for the treatment of a broad range of cognitive disorders.

Schizophrenia is a chronic, severe, and disabling brain disease. Approximately 1% of the population develops schizophrenia during their lifetime and more than 2 million Americans suffer from the illness in a given year. Early on in the course of disease schizophrenics suffer "gating" defects rendering them unable to filter out unimportant stimuli thereby compromising attention focus and thought processes. Under normal circumstances sensory responses are inhibited when preceded by a weaker stimulus, a phenomenon known as pre-pulse inhibition. This process which is a measure of gating defects is impeded in schizophrenia patients, possibly due to neurodevelopmental events and is reversed by some antipsychotics. As disease progresses schizophrenics develop a range of symptoms which are broadly divided into positive (including hallucinations and delusions) and negative (including apathy and withdrawal) symptoms.

Second generation antipsychotics remain a mainstay of treatment for schizophrenia and continue to drive the antipsychotic market with a growth rate of 27.2% between 2002-2003. The antipsychotic market is worth an estimated $10.7 billion and is led by Eli Lilly's blockbuster Zyprexa. After 2007, the market is expected to plateau due to the genericization of Janssen's Risperdal and Pfizer's Geodon. However, Bristol-Myers Squibb's dopaminergic modulator Abilify is predicted to reach blockbuster status by 2009. Launched in 2002 Abilify is able to treat both the positive and negative symptoms of schizophrenia and has achieved good uptake (for an evaluation of antipsychotics click here). Despite success in this area of treatment control, the ability of available medications to reverse cognitive impairments in schizophrenia, an important contribute to the disability associated with the disease, remains controversial. If ABT-239 were to demonstrate effective antipsychotic activity as well as cognitive improvement it would therefore have significant potential advantages over current treatments. Therefore as well as evaluating ABT-239 in models of cognition, Fox et al also investigated the effects of this molecule in various models of schizophrenia.

Like patients with schizophrenia DBA/2 mice exhibit defects in the pre-pulse inhibition of the startle response. This defect was reversed by ABT-239, an effect resembling that produced by nicotine which is effective in schizophrenia patients. ABT-239 also blocked the psychostimulant effects of methamphetamine, a model of the positive symptoms of schizophrenia. Importantly however this was without the sedative or cataleptogenic effects of risperidone.

In summary therefore ABT-239 represents a promising agent for the treatment of a variety of CNS disorders. Primarily this candidate appears to be of potential use in the treatment of cognitive components of ADHD, Alzheimer's and schizophrenia. Cognitive impairment is an important yet unmet component of schizophrenia, and the promise of ABT-239 in the treatment of this disease is even greater given its ability to improve measure of positive symptomology associated with schizophrenia

Entry date Thursday, January 20, 2005

J Pharmacol Exp Ther. 2004 Dec 17; [Epub ahead of print]