Dodecyl creatine ester, a promising treatment to deliver creatine to neurons, achieves pharmacology efficacy in creatine transporter deficiency

IF 6 2区 医学 Q1 CHEMISTRY, MEDICINAL European Journal of Medicinal Chemistry Pub Date : 2024-12-20 DOI:10.1016/j.ejmech.2024.117195
Clémence Disdier, Clara Lhotellier, Anne-Cécile Guyot, Narciso Costa, Frédéric Théodoro, Alain Pruvost, Matthew R. Skelton, Thomas Joudinaud, Aloïse Mabondzo, Henri Bénech
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Abstract

Dodecyl creatine ester (DCE) is a creatine prodrug currently developed for brain diseases, including creatine transporter deficiency (CTD), an incurable rare genetic disease. A dual strategy combining a prodrug to bypass the non-functional creatine transporter and its delivery via the nose-to-brain pathway has been proposed to replenish creatine levels in cerebral cells, particularly in neurons of CTD patients. In vitro and in vivo studies in various animal models, including wild-type non-human primates and creatine transporter deficient mice, show that formulated DCE, when administered intranasally, achieves significant cerebral distribution up to the target cells, the neurons, and modulates the expression of neuronal markers related to cognitive function at doses intended for patients.These compelling results contribute to a better understanding of the pharmacokinetics and pharmacodynamics of DCE after nasal administration, with a particular focus on the crucial role of the nose-to-brain pathway in DCE distribution.

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来源期刊
CiteScore
11.70
自引率
9.00%
发文量
863
审稿时长
29 days
期刊介绍: The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.
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