A Novel Parkinson’s Disease Drug Candidate with Potent Anti-neuroinflammatory Effects through the Src Signaling Pathway

Numerous drug treatments
are available for Parkinson’s disease
(PD), an age-related neurodegenerative disease, but most cause serious
side effects. Therefore, novel therapeutic strategies that halt disease
progression and allow for long-term administration are urgently needed.
Neuroinflammation critically contributes to the pathogenesis of PD.
Here, we report the discovery and optimization of phloroglucinol derivatives,
a novel class of anti-neuroinflammatory compounds. Structural modifications
of the hit compound 3-methyl-1-(2,4,6-trihydroxyphenyl)­butan-1-one
produced 43 derivatives, including a preclinical candidate (compound 21), that exhibited potent in vitro anti-neuroinflammatory
effects, good blood–brain barrier penetration, and desirable
safety margins in mice at a median lethal dose (LD50) >5000
mg/kg. Its in vivo efficacy was demonstrated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP)- and MPTP/probenecid (prob)-induced subacute and chronic PD
models, respectively, and α-synuclein transgenic mice. Mechanistic
studies revealed neuroinflammation inhibition by targeting Src/phosphatase
and tensin homologue deleted on chromosome 10 (PTEN)/Akt signaling
might be promising. We highlighted the potential usefulness of phloroglucinol
derivatives in PD treatment.