Central Nervous System Disorders - Cognitive Impairment

AMRI has discovered a number of novel 5-HT6 modulators with good in vitro profiles, which could potentially treat Alzheimer’s disease and schizophrenia. The modulators have shown very good 5-HT6 affinity (Ki <10 nM), excellent metabolic stability, good solubility and a highly acceptable off-target profile.

Cognitive function, which underpins all of our everyday activities, is defined as the complicated mental processes that are involved in attending to, acquiring, storing, retrieving and manipulating information. In cases of cognitive impairment, some (or all) of the aforementioned processes are affected resulting in difficulty when dealing with new information or situations.

Cognitive impairment is a major problem worldwide, and is associated with diseases such as Alzheimer’s and schizophrenia. There is currently a highly significant unmet need for treating cognitive impairment in the aforementioned disease populations. Thus, there is a demand for an agent that can be taken as an adjunct therapy with current antipsychotic medications to improve cognitive function in schizophrenics, or as a stand alone to treat the symptoms of Alzheimer’s disease.

Understanding the 5-HT6 Receptor

The 5-HT6 receptor is one of the 14 serotonin receptors that have been reported. It is distributed almost exclusively in the CNS. Antagonism of this receptor has been shown to elicit positive effects on animal models of cognition, and a number of such antagonists have progressed to clinical trials for cognition-related disorders.

Furthermore, recent data has provided compelling evidence that 5-HT6 modulators can cause a lowering of body weight and food intake in overweight rats that surpass that of the currently marketed drugs sibutramine and rimonabant. AMRI is exploring this evidence in concurrent research for obesity treatment.