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

• Published in: Journal of medicinal chemistry 2016-10, Vol.59 (19), p.9062-9079
• Main Authors: Wang, Ya-Dan, Bao, Xiu-Qi, Xu, Song, Yu, Wen-Wen, Cao, Sheng-Nan, Hu, Jin-Ping, Li, Yan, Wang, Xiao-Liang, Zhang, Dan, Yu, Shi-Shan
• Format: Article
• Language: English
• Subjects: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Disease Models, Animal; Drug Discovery; Male; Mice, Inbred ICR; Mice, Transgenic; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Parkinson Disease, Secondary - drug therapy; Parkinson Disease, Secondary - metabolism; Parkinson Disease, Secondary - pathology; Phloroglucinol - analogs & derivatives; Phloroglucinol - chemistry; Phloroglucinol - pharmacology; Phloroglucinol - therapeutic use; Serine - analogs & derivatives; Serine - chemistry; Serine - pharmacology; Serine - therapeutic use; Signal Transduction - drug effects; src-Family Kinases - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.6b00976

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.