A relevant excerpt from the patent application:
>There is no cure for PD. Current therapy relies heavily on replenishing dopamine by giving patients oral doses of a dopaminergic agent like the dopamine precursor levodopa (alone or in the combination carbidopa levodopa) or a dopamine agonist. Such therapy can provide relief, although with the increasing risk of serious side effects and often with diminishing therapeutic results, requiring increasing doses as treatment continues, and more serious side effects. There is a profound need for additional therapeutics for PD.
c-Abl is a major regulator of parkin function and phosphorylates parkin on tyrosine 143. This phosphorylation inhibits parkin's E3 ubiquitin ligase activity leading to
accumulation of AIMP2 and FBP1 and loss of parkin's cytoprotective function and cell death. One Abl inhibitor, STI-571 , has been found to maintain parkin in a catalytically active and neuroprotective state by preventing phosphorylation of parkin. As such, it is believed that inhibition of c-Abl presents a viable approach for the treatment of PD. o, et al., PNAS, 107(38), 16691 -16696 (2010). One challenge of using STI-571 to treat PD is that it has poor penetration of the blood-brain barrier as demonstrated in mice and humans. Thus, there is a need for Abl inhibitors that cross the blood-brain barrier for the treatment of PD.
Applicant's own WO 2007/075869, which is hereby incorporated herein by reference for all purposes, discloses certain compounds that inhibit inter alia Abl. One notable Abl inhibitor is ponatinib, which is currently the subject of a clinical trial to determine the efficacy of ponatinib in patients with chronic myeloid leukemia (CML) in chronic phase (CP), accelerated phase (AP) or blast phase (BP) or with Ph positive (Ph+) acute lymphoblastic leukemia (ALL) who either are resistant or intolerant to either dasatinib or nilotinib, or have the T315I mutation of Bcr-Abl (clinical trials.gov identifier NCT01207440). WO 2007/075869 does not explicitly mention using such Abl inhibitors for the treatment of PD.
SUMMARY
It has been unexpectedly discovered that certain Abl inhibitors cross the blood brain barrier and are useful in the regulation of parkin and accordingly for the treatment of PD.<
