An improved L-DOPA-like compound for treatment of Parkinson's Disease and related movement disorders
Description: L-DOPA in fixed combinations with a peripherally active DOPA decarboxylase inhibitors (DDI) to date is the gold standard in the treatment of Parkinsonīs Disease (PD). The rationale for this treatment is to locally limit the generation of Dopamine (DA) by decarboxylation of L-DOPA to the brain. The L-DOPA/DDI treatment usually provides a sustained clinical benefit and up to now is the only PD treatment, which proved to prolong life expectancy of PD patients. However, L-DOPA exhibits a wide range of inter- and intra-patient variations in the rate and extent of absorption. Furthermore, disabling motor effects such as dyskinesia and motor fluctuations and certain toxic effects develop at chronic L-DOPA therapy and limit its long-term use. Structual fluctuations of dopamine seem to be closely related to dyskinesias, and "on-off"-phenomene, especially in late stage PD patients at high L-Dopa doses. When systemic modification of the L-Dopa, and dopamine metabolism were introduced, BDD-20617 at the first time modified PK of striatal dopamine directly. Additionally, there are non-motor complications such as autonomic dysfunctions and psychiatric complications and cardiovascular side effects, which are supposed to be related to the metabolism of L-DOPA to norepinephrine (NE) and epinephrine. Direct DA agonists and selective DA reuptake inhibitors are the actual R&D mainstream and likely to become the drugs of first choice in the treatment of PD. However, there are still substantial questions to be answered. Within the next 10-15 years L-DOPA will remain an essential part of the PD therapy. BDD-20617 is a L-DOPA-like compound that emerged from the BDD/CDRD Groupīs Atomic Substitution Technology platform and addresses current drawbacks of L-DOPA while simultaneously keeping all its advantageous features. With respect of its binding properties to various dopamine receptors, BDD-20617-DA does not differ from endogenous DA. Administration of BDD-20617 in reserpine treated rats, an established PD animal model, leads to a significant increase in locomotor activity compared to classical L-DOPA treatment. Due to the higher efficacy of BDD-20617-DA a reduced daily dose of BDD-20617 for the therapy of PD patients is expected that will diminish the overall catecholamine load and is unambiguously beneficial for long-term treatment. Furthermore, the rate of neuronal biodegradation of BDD-20617-DA to NE is reduced to about 40% as compared to endogenous DA. From our experience with the atomic substitution technology we expect BDD-20617 to exhibit an improved passage through the blood-brain barrier and to be more resistant to oxidation than endogenous DA. Thus, BDD-20617 might lead to a diminished risk of long-term pro-degenerative effects due to iatrogenic cytosolic excess of autoxidative products of catecholamines. Overall, BDD-20617 is likely to exhibit in higher efficacy for PD treatment, less acute NE associated side effects and less oxidative neurotoxicity as compared to current L-DOPA. |
