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Molecules 2016, 21(4), 488; doi:10.3390/molecules21040488

Design, Synthesis and Biological Evaluation of Brain-Targeted Thiamine Disulfide Prodrugs of Ampakine Compound LCX001

Laboratory of Computer-Aided Drug Design & Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
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Author to whom correspondence should be addressed.
Academic Editor: Jean Jacques Vanden Eynde
Received: 26 February 2016 / Revised: 30 March 2016 / Accepted: 8 April 2016 / Published: 14 April 2016
(This article belongs to the Section Medicinal Chemistry)
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Abstract

Ampakine compounds have been shown to reverse opiate-induced respiratory depression by activation of amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors. However, their pharmacological exploitations are hindered by low blood-brain barrier (BBB) permeability and limited brain distribution. Here, we explored whether thiamine disulfide prodrugs with the ability of “lock-in” can be used to solve these problems. A series of thiamine disulfide prodrugs 7a–7f of ampakine compound LCX001 was synthesized and evaluated. The trials in vitro showed that prodrugs 7e, 7d, 7f possessed a certain stability in plasma and quickly decomposed in brain homogenate by the disulfide reductase. In vivo, prodrug 7e decreased the peripheral distribution of LCX001 and significantly increased brain distribution of LCX001 after i.v. administration. This compound showed 2.23- and 3.29-fold greater increases in the AUC0-t and MRT0-t of LCX001 in brain, respectively, than did LCX001 itself. A preliminary pharmacodynamic study indicated that the required molar dose of prodrug 7e was only one eighth that of LCX001 required to achieve the same effect in mice. These findings provide an important reference to evaluate the clinical outlook of ampakine compounds. View Full-Text
Keywords: opiate; respiratory depression; ampakines; thiamine disulfide prodrugs; brain distribution opiate; respiratory depression; ampakines; thiamine disulfide prodrugs; brain distribution
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Xiao, D.; Meng, F.-H.; Dai, W.; Yong, Z.; Liu, J.-Q.; Zhou, X.-B.; Li, S. Design, Synthesis and Biological Evaluation of Brain-Targeted Thiamine Disulfide Prodrugs of Ampakine Compound LCX001. Molecules 2016, 21, 488.

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