Development of L-745,870, a Selective D4 Receptor Antagonist, for the Treatment of Levodopa-induced Dyskinesia

Objective/Rationale: 
In the 1980s and 90s a novel drug, L-745,870 was developed for the treatment of psychosis in schizophrenia. L-745,870 has excellent characteristics for a drug, and a selective action to block signalling at D4 dopamine receptors. It was found to be safe and well-tolerated in human but was ineffective against psychosis, so its development was terminated. In the last year, we found that L-745,870 reduces the problem of levodopa-induced dyskinesia in pre-clinical models with parkinsonism. We propose to resurrect the development of L-745,870 and move it forward as a treatment for dyskinesia in PD.

Project Description:             
We have generated a development plan for rapid transition to a proof-of-concept clinical trial.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:                     
Levodopa-induced dyskinesia remains one of the major factors limiting the usefulness of current treatments for Parkinson’s disease. The program has potential to provide a pharmacological means to reduce the impact of dyskinesia on the quality of life of people with PD.

Anticipated Outcome:          
If successful the program will define safety and appropriate doses of L-745,870. It will demonstrate the ability of L-745,870 to reduce Levodopa-induced dyskinesia in a small, well-controlled clinical trial in patients with PD. We will thus provide a drug product that can be further assessed for safety and effectiveness in larger trials.