R(+) Pramipexole

Treatment classes: Small Molecule

Synonyms: Pramipexole=S(-) PPX,Mirapex®, Mirapexin® Sifrol®; R(+)PPX= SND919CL2x
Development Status: Approved US, Phase II

Pipeline Status: Closeout

Disease Indications: R(+)PPX is in Ph II for ALS. The (-) stereoisomer of pramipexole is FDA approved for Antiparkinsonian, dopaminergic
Manufacturers: Jim Bennett
Targets: mitochondrial permeability transition pore

Rationale for ALS: The dopamine agoinst Mirapex (the (-) stereoisomer of pramipexole) is also an inhibitor of the mitochondrial permeability transition pore. The permeability transition pore in the inner mitochondrial membrane is known to play a role in the apoptotic signaling cascade and blocking the permeability transition pore may have a neuroprotective effect. In fact, Mirapex has been shown to protect neuronal cells from apoptosis. However, due to Mirapex’s high affinity for the D2 dopamine receptor, its dosage for effective neuroprotection would have too many side effects. James Bennett (of Univ. Virginia) noticed the (+) stereoisomer of pramipexole (R(+)PPX) still has the same neuroprotective effects but has 100-fold less affinity for dopamine receptors, and could therefore be used at a much higher dosage, and proposed its use as a therapy for ALS. It has also been shown to reduce oxidative stress in ALS patients (4) and SOD1G93A mice (5).


Title: Use of pramipexole to treat amyotrophic lateral sclerosis
Document Type and Number: United States Patent 7157480
Link to this Page: http://www.freepatentsonline.com/7157480.html
Abstract: The present invention is directed to compositions comprising pramipexole and the use of such compositions to treat neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). As shown in FIG. 6B the mean +/- SEM serum 2,3-DHBA levels for the 12 ALS participants decreased significantly after pramipexole treatment.


July 19, 2006
Variant of Parkinson’s Drug Tested In ALS
Investigators at the University of Virginia in Charlottesville are testing a compound known as R(+) pramipexole in people with amyotrophic lateral sclerosis (ALS) to see whether it alters their decline in function or changes biochemical markers of the cell-damaging process known as oxidative stress.
James Bennett, a professor of neurology at the University of Virginia School of Medicine, became interested in testing R(+) pramipexole in ALS a few years ago, after S(-) pramipexole, whose structure is a mirror image of the R form, was found effective in Parkinson’s disease.
S(-) pramipexole was developed into the drug Mirapex, which mimics the brain chemical dopamine and acts as an antioxidant, combatting oxidative stress. It enters the nervous system and the mitochondria, the sites of energy generation inside cells.
Bennett, a physician who has a doctoral degree in pharmacology, recently found that 15 ALS patients tolerated 30 milligrams a day of R(+) pramipexole, which does everything the S(-) form does except mimic dopamine, which isn’t a goal in ALS treatment.
Thirty milligrams is about five times the tolerable dose of the S form, says Bennett, who’s now testing one ALS patient at a time to see how high he can boost the dose of the R form.
The investigators aren’t seeking new trial participants at this time, but they may be in the future.
“So far the results are encouraging for slowing disease progression,” Bennett says, “but there aren’t enough data yet to draw any firm conclusions.”
For more information, see R(+) Pramipexole in Early ALS.