Clinical trials are still under way for these compounds.
.......................................................
Eur J Pharmacol 2001 Mar 16;415(2-3):173-80
Failure of GPI compounds to display neurotrophic activity in vitro and in vivo.
Bocquet A, Lorent G, Fuks B, Grimee R, Talaga P, Daliers J, Klitgaard H.
Preclinical CNS Research, UCB S.A. Pharma Sector, Chemin du Foriest, B-1420,
Braine-l'Alleud, Belgium
The aim of this study was to evaluate the neurotrophic and neuroprotective
properties of a series of immunophilin ligands and to assess the potential
involvement of FK506 Binding Protein 12 kDa (FKBP12) rotamase inhibition in this
activity. Both FK506 and rapamycin induced a potent inhibition of the FKBP12
rotamase activity (pIC(50) values of 7.3 and 7.4, respectively) but only a
modest inhibition was observed with
1-(3,3-dimethyl-2-oxo-pentanoyl)-pyrrolidine-2-carboxylic acid
S-3-pyridin-3-yl-propyl ester (GPI 1046) (5.8), its N-oxide (5.4) and thioester
(6.3) analogues. Compared to nerve growth factor, all these immunophilin ligands
only induced marginal increases in neurite outgrowth of rat dissociated newborn
dorsal root ganglia cells. Furthermore, systemic administration of GPI 1046 and
its N-oxide and thioester analogues failed to prevent striatal dopamine
depletion induced by acute or chronic i.p. treatment with 1-methyl-4-phenyl
1,2,3,6 tetrahydropyridine (MPTP). These results suggest that inhibition of
FKBP12 rotamase activity is not predictive for neurotrophic and neuroprotective
properties of immunophilin ligands and question their therapeutic utility in
neurodegenerative diseases like Parkinson's disease.
PMID: 11274996 [PubMed - indexed for MEDLINE]
.......................................................
Ray Strand
Prairie Sky Design
-----------------( on the Edge of the Prairie Abyss )---------------
when the sky is clear
the ground is visible
49/dx PD 2 yrs/40? onset/retired
----------------------------------------------------------------------
To sign-off Parkinsn send a message to: mailto:[log in to unmask]
In the body of the message put: signoff parkinsn
