Chlorion is actively developing two small molecule compounds, CLP635 and CL-301, which modulate cation-chloride co-transporters as a means to quell neuronal hyperactivity in the central nervous system.

CLP635 is under development for the treatment of neuropathic pain and partial seizures, whereas indications for CL-301 have yet to be determined. Note that based on recent profiling of CL-301, we believe that it may demonstrate utility in both neurological and psychiatric disorders.

Both CLP635 and CL-301 have demonstrated superior efficacy and safety in experimental models.

Over several years, scientists affiliated with Chlorion have examined the role of chloride homeostasis in the induction and maintenance of states of neuronal hyperexcitability, which is a hallmark of many neurological and psychiatric disorders.

Under normal circumstances, the excitability of neurons in key regions of the central nervous system is kept in check by the GABAergic and glycinergic neurotransmitter systems, which effect inhibition by controlling the movement of chloride into the neuron.

In states of disease, including neuropathic painNeuropathic pain is defined by the International Association for the Study of Pain (IASP) as a form of chronic pain that is caused by a lesion or dysfunction of the nervous system. and epilepsyEpileptic disorder (epilepsy) is defined by the International League Against Epilepsy as a chronic neurological condition characterized by recurrent epileptic seizures. and bipolar diseaseBipolar disease, also known as manic-depressive disease, is defined by the National Institutes of Health as a depressive disorder in which a person alternates between episodes of major depression and mania (periods of abnormally and persistently elevated mood)., scientists have shown that chloride homeostasis is disrupted, leading to a situation whereby the GABAergic and glycinergic systems no longer effectively mediate inhibition.

Such aberrant chloride equilibrium is triggered by the dysfunction of chloride transporters, typically passive channels located in neuronal membranes.

For more information on mechanisms of chloride disequilibrium, please see Coull et al., Nature, 2003.

Chlorion’s therapeutic strategy for neuropathic pain, epilepsy and other indications involves quelling hyperactivity in the central nervous system by correcting neuronal chloride imbalances. This is accomplished by directly modulating the activity of cation-chloride co-transporters, which are responsible for maintaining the equilibrium of chloride inside the cell.

The company believes that this strategy will lead to first-in-class therapeutics superior to those in late-stage clinical development or on the market today in terms of:

• Mean effectiveness;
• Adverse event profile; and
• Inter-individual variability of response.

To date, Chlorion has developed a broad library of novel small molecules that effectively modulate chloride in neurons, via selective actions on various chloride co-transporters including KCC2, KCC4 and NKCC1. Many of the small molecules have demonstrated robust utility in in vivo experimental models of various disorders of the central nervous system.