Cannabidiol (CBD 1) is a nonpsychotic cannabinoid-based drug approved by the U.S. FDA for treating refractory epilepsy, namely, Lennox-Gastaut and Dravet syndrome. However, its low aqueous solubility and oral bioavailability are compensated by administering high doses, and there is an increased demand for conjugates with improved properties. In this direction, the present work is focused on synthesizing CBD-based prodrugs to address the issue of poor solubility and oral bioavailability. Several CBD-based prodrugs were synthesized and studied in a battery of assays: viz, release kinetic (ex vivo), solubility (in vitro), chemical stability (in vitro), plasma stability (ex vivo), pharmacokinetics (in vivo), and efficacy studies (in vivo). Among the synthesized prodrugs, the morpholinyl CBD-based prodrugs 3a and 3aa showed good release behavior, stability, better solubility, and a plasma profile. Moreover, prodrug candidate 3aa showed better therapeutic efficacy. The present study identifies CBD-based prodrugs with improved physiochemical properties and oral exposure.
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