title: Synthesis and biological evaluation of new creatine fatty esters revealed dodecyl creatine ester as a promising drug candidate for the treatment of the creatine transporter deficiency.
abstract: The creatine transporter deficiency is a neurological disease caused by impairment of the creatine transporter SLC6A8, resulting in mental retardation associated with a complete absence of creatine within the brain and cellular energy perturbation of neuronal cells. One of the therapeutic hypotheses was to administer lipophilic creatine derivatives which are (1) thought to have better permeability through the cell membrane and (2) would not rely on the activity of SLC6A8 to penetrate the brain. Here, we synthesized creatine fatty esters through original organic chemistry process. A screening on an in vitro rat primary cell-based blood-brain barrier model and on a rat primary neuronal cells model demonstrated interesting properties of these prodrugs to incorporate into endothelial, astroglial, and neuronal cells according to a structure-activity relationship. Dodecyl creatine ester showed then a 20-fold increase in creatine content in pathological human fibroblasts compared with the endogenous creatine content, stating that it could be a promising drug candidate.
authors.affiliation: CEA, DSV, iBiTec-S, Service de Pharmacologie et d'Immunoanalyse, 91191 Gif sur Yvette, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Trotier-Faurion
authors.forename: Sophie
authors.initials: S
authors.lastname: Dézard
authors.forename: Frédéric
authors.initials: F
authors.lastname: Taran
authors.forename: Vassili
authors.initials: V
authors.lastname: Valayannopoulos
authors.forename: Pascale
authors.initials: P
authors.lastname: de Lonlay
authors.forename: Aloïse
authors.initials: A
authors.lastname: Mabondzo
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D003401:Creatine / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D003404:Creatinine / Q000737:chemistry; D004355:Drug Stability; D004952:Esters; D005260:Female; D006801:Humans; D026901:Membrane Transport Proteins / Q000172:deficiency*; D011247:Pregnancy; D051381:Rats
chemical_list: D004952:Esters; D026901:Membrane Transport Proteins; C080679:creatine transporter; D003404:Creatinine; D003401:Creatine