title: Evaluation of 2-thioxo-2,3,5,6,7,8-hexahydropyrimido[4,5-d]pyrimidin-4(1H)-one analogues as GAA activators.
abstract: 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.
authors.affiliation: NIH Chemical Genomic Center, National Human Genome Research Institute, National Institutes of Heath, 9800 Medical Center Drive, Rockville, MD, USA. maruganj@mail.nih.gov
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Marugan
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.forename: Omid
authors.initials: O
authors.lastname: Motabar
authors.forename: Noel
authors.initials: N
authors.lastname: Southall
authors.forename: Ehud
authors.initials: E
authors.lastname: Goldin
authors.forename: Ellen
authors.initials: E
authors.lastname: Sidransky
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Aungst
authors.forename: Ke
authors.initials: K
authors.lastname: Liu
authors.forename: Subir Kumar
authors.initials: SK
authors.lastname: Sadhukhan
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Austin
mesh_terms: D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000520:alpha-Glucosidases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D020536:Enzyme Activators; D011744:Pyrimidinones; D000520:alpha-Glucosidases