Evaluation of 2-thioxo-2,3,5,6,7,8-hexahydropyrimido[4,5-d]pyrimidin-4(1H)-one analogues as GAA activators.

Rare Disease
Medicinal Chemistry


Pompe disease is a lysosomal storage disease (LSD) caused by a deficiency in the lysosomal enzyme acid alpha-glucosidase. In several LSDs, enzyme inhibitors have been used as small molecule chaperones to facilitate and increase the translocation of mutant protein from the endoplasmic reticulum to the lysosome. Enzyme activators with chaperone activity would be even more desirable as they would not inhibit the enzyme after translocation and might potentiate the activity of the enzyme that is successfully translocated. Herein we report our initial findings of a new series of acid alpha-glucosidase activators.


Marugan, Juan; Zheng, Wei; Motabar, Omid; Southall, Noel; Goldin, Ehud; Sidransky, Ellen; Aungst, Ronald A; Liu, Ke; Sadhukhan, Subir Kumar; Austin, Christopher;


  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Enzyme Activation/ drug effects
  • Enzyme Activators/ chemical synthesis
  • Enzyme Activators/ chemistry
  • Enzyme Activators/ pharmacology
  • Molecular Structure
  • Pyrimidinones/ chemical synthesis
  • Pyrimidinones/ chemistry
  • Pyrimidinones/ pharmacology
  • Stereoisomerism
  • Structure-Activity Relationship
  • alpha-Glucosidases/ chemistry
  • alpha-Glucosidases/ metabolism

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