Advanced preclinical GlyT-1 inhibitor for the treatment of LID in Parkinson's disease.
CSTI-200 is an advanced preclinical development candidate that holds great potential for the treatment of LID in Parkinson's disease. It is a potent and selective inhibitor of GlyT-1, and is characterized by favorable pharmacological and ADMET properties. Our research has demonstrated that CSTI-200 is readily absorbed orally, is CNS penetrant, and effectively binds to GlyT-1 in the forebrain. This drug's competitive mechanism of action provides a "self-regulating" property and offers the potential for improved tolerability compared to non-competitive GlyT-1 inhibitors.
Aberrant glutamatergic neurotransmission in the nigrostriatal system has been linked to PD progression and LID emergence. To treat LID, many drug discovery strategies are focusing on modulating glutamatergic targets to regulate basal ganglia DA neurotransmission. Amantadine's anti-dyskinetic effects are thought to be largely due to its modulation of striatal glutamatergic neurotransmission via NMDAR antagonism. Glutamate receptor modulators have been shown to reduce LID severity in patients and non-human primates and prevent LID in animal models. Stimulating NMDAR activity by increasing D-serine or glycine concentrations has also been shown to effectively alleviate LID, as demonstrated in a pilot clinical trial with D-serine.
We believe that CSTI-200 is a potentially ideal GlyT1 inhibitor that can be used to treat debilitating LID. We are striving to provide this potentially breakthrough therapy to patients in need.
Preclinical and clinical evidence also suggests that GlyT-1 inhibition may be a promising therapeutic approach in advanced Parkinson's disease for treating not only LID, but also motor fluctuations, and PD psychosis. The potential for a single therapeutic agent to effectively address these three features could be a major advancement in Parkinson's treatment and improve quality of life for patients. Current treatments often alleviate one feature while exacerbating another.