H3 antagonists

Target and Target Class: Histamine 3 (H3) receptor, GPCR

Indication: Diseases associated with cognitive impairment (Alzheimer's disease, schizophrenia), sleep disorders (narcolepsy), pain, eating disorders

Rationale

The histamine system constitutes one of the most important brain-activating systems regulating several brain functions. While, in the brain, histamine exerts its stimulatory action through post-synaptic H1 and H2 histamine receptor subtypes, H3 receptors are located presynaptically inhibiting histamine release. H3 receptor expression is not confined to histaminergic neurons, but, as a heteroreceptor on other neuron types, the H3 receptor is known to modulate various neurotransmitter systems in the brain, such as acetylcholine, dopamine and noradrenaline.

Schematic representation of H3 receptor function.

Stimulation of presynaptic H3 autoreceptors on histaminergic neurons by histamine (HA) inhibits the synthesis of histamine through histidine decarboxylase (HDC) and also inhibits the release of HA from the neuron. Similarly, stimulation of presynaptic H3 heteroreceptors on non-histaminergic neurons inhibits the release of a number of neurotransmitters (NT), including norepinephrine (NE, noradranaline), acetylcholine (ACh), serotonin (5HT), dopamine (DA), and others. (Reproduced with permission from Timothy A. Esbenshade et al. (2006) Molecular Intervention 6, 77-88).

As impairment in certain neurotransmitter systems is involved in neurological and psychiatric disorders, and given the modulatory effects of H3 receptors on multiple neurotransmitter systems, H3 antagonists are potential therapeutic agents for a variety of diseases such as Alzheimer's disease, narcolepsy and neuropathic pain. Data obtained with H3 antagonists as well as with H3 receptor knock-out models have provided a plethora of information on H3 receptor function and strengthen the rationale for H3 antagonists in these therapeutic indications.

Evotec's attention is currently focused on memory and cognition with the purpose of developing a compound for Alzheimer's disease and other medical conditions associated with cognitive dysfunction. Evotec is also exploring the potential of H3 antagonists in narcolepsy, a disorder of sleep regulation characterized by excessive daytime sleepiness and fatigue with sudden and uncontrollable urges to sleep

Status

Evotec has identified and optimized novel and highly selective classes of small molecule antagonists of the histamine H3 receptor. Members of the active series' have been tested in relevant in vivo models and have been shown to have promising profiles for progressing to the stage of preclinical development candidates. The lead series is estimated to be 6 months from the start of preclinical development. Evotec would be interested in discussing partnering opportunities for this interesting program.