13 research outputs found
Deuteration and fluorination of 1,3-bis(2-phenylethyl)pyrimidine-2,4,6(1H,3H,5H)-trione to improve its pharmacokinetic properties
Cyclohexane 1,3-diones and their inhibition of mutant SOD1-dependent protein aggregation and toxicity in PC12 cells
Arylazanylpyrazolone Derivatives as Inhibitors of Mutant Superoxide Dismutase 1 Dependent Protein Aggregation for the Treatment of Amyotrophic Lateral Sclerosis
The
arylsulfanylpyrazolone and aryloxanylpyrazolone scaffolds previously
were reported to inhibit Cu/Zn superoxide dismutase 1 dependent protein
aggregation and to extend survival in the ALS mouse model. However,
further evaluation of these compounds indicated weak pharmacokinetic
properties and a relatively low maximum tolerated dose. On the basis
of an ADME analysis, a new series of compounds, the arylazanylpyrazolones,
has been synthesized, and structure–activity relationships
were determined. The SAR results showed that the pyrazolone ring is
critical to cellular protection. The NMR, IR, and computational analyses
suggest that phenol-type tautomers of the pyrazolone ring are the
active pharmacophore with the arylazanylpyrazolone analogues. A comparison
of experimental and calculated IR spectra is shown to be a valuable
method to identify the predominant tautomer
ADME-Guided Design and Synthesis of Aryloxanyl Pyrazolone Derivatives To Block Mutant Superoxide Dismutase 1 (SOD1) Cytotoxicity and Protein Aggregation: Potential Application for the Treatment of Amyotrophic Lateral Sclerosis
Amyotrophic lateral sclerosis (ALS) is an orphan neurodegenerative
disease currently without a cure. The arylsulfanyl pyrazolone (ASP)
scaffold was one of the active scaffolds identified in a cell-based
high throughput screening assay targeting mutant Cu/Zn superoxide
dismutase 1 (SOD1) induced toxicity and aggregation as a marker for
ALS. The initial ASP hit compounds were potent and had favorable ADME
properties but had poor microsomal and plasma stability. Here, we
identify the microsomal metabolite and describe synthesized analogues
of these ASP compounds to address the rapid metabolism. Both in vitro
potency and pharmacological properties of the ASP scaffold have been
dramatically improved via chemical modification to the corresponding
sulfone and ether derivatives. One of the ether analogues (<b>13</b>), with superior potency and in vitro pharmacokinetic properties,
was tested in vivo for its pharmacokinetic profile, brain penetration,
and efficacy in an ALS mouse model. The analogue showed sustained
blood and brain levels in vivo and significant activity in the mouse
model of ALS, thus validating the new aryloxanyl pyrazolone scaffold
as an important novel therapeutic lead for the treatment of this neurodegenerative
disorder
Proteasome Activation is a Mechanism for Pyrazolone Small Molecules Displaying Therapeutic Potential in Amyotrophic Lateral Sclerosis
Amyotrophic
lateral sclerosis (ALS) is a progressive and ultimately
fatal neurodegenerative disease. Pyrazolone containing small molecules
have shown significant disease attenuating efficacy in cellular and
murine models of ALS. Pyrazolone based affinity probes were synthesized
to identify high affinity binding partners and ascertain a potential
biological mode of action. Probes were confirmed to be neuroprotective
in PC12-SOD1<sup>G93A</sup> cells. PC12-SOD1<sup>G93A</sup> cell lysates
were used for protein pull-down, affinity purification, and subsequent
proteomic analysis using LC-MS/MS. Proteomics identified the 26S proteasome
regulatory subunit 4 (PSMC1), 26S proteasome regulatory subunit 6B
(PSMC4), and T-complex protein 1 (TCP-1) as putative protein targets.
Coincubation with appropriate competitors confirmed the authenticity
of the proteomics results. Activation of the proteasome by pyrazolones
was demonstrated in the absence of exogenous proteasome inhibitor
and by restoration of cellular protein degradation of a fluorogenic
proteasome substrate in PC12-SOD1<sup>G93A</sup> cells. Importantly,
supplementary studies indicated that these molecules do not induce
a heat shock response. We propose that pyrazolones represent a rare
class of molecules that enhance proteasomal activation in the absence
of a heat shock response and may have therapeutic potential in ALS