Chiral cyclohexane 1,3-diones as inhibitors of mutant SOD1-dependent protein aggregation for the treatment of ALS

Yinan Zhang, Radhia Benmohamed, Wei Zhang, Jinho Kim, Christina K. Edgerly, Yaoqiu Zhu, Richard I. Morimoto, Robert J. Ferrante, Donald R. Kirsch, Richard B. Silverman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Cyclohexane 1,3-diones were identified as a class of molecules exhibiting a protective effect against mutant SOD1 induced toxicity in PC-12 cells, but an optimized analogue had little or no effect on life extension in the G93A SOD1 mouse model for amyotrophic lateral sclerosis (ALS). Additional testing showed that these compounds were inactive in neurons, and further analogue synthesis was carried out to identify compounds with neuronal activity. Starting from two racemic derivatives that were active in cortical neurons, two potent analogues (1b and 2b) were resolved, which were protective against mutant SOD1 induced toxicity in PC-12 cells. Both compounds were found to be active in cortical neurons and presented good ADME profiles in vitro. On the basis of these results, an ALS mouse trial with 1b was carried out, which showed slightly greater life extension than the FDA-approved ALS drug riluzole, thereby validating cyclohexane 1,3-diones as a novel therapeutic class for the treatment of ALS.

Original languageEnglish (US)
Pages (from-to)584-587
Number of pages4
JournalACS Medicinal Chemistry Letters
Volume3
Issue number7
DOIs
StatePublished - Jul 12 2012

Keywords

  • Cyclohexane 1,3-diones
  • PC-12 cells
  • amyotrophic lateral sclerosis (ALS)
  • cortical neurons
  • mutant SOD1
  • protein aggregation
  • superoxide dismutase 1 (SOD1)

ASJC Scopus subject areas

  • Drug Discovery
  • Biochemistry
  • Organic Chemistry

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