Synthesis, in vitro and in vivo characterization of novel ethyl dioxy phosphate prodrug of propofol.

A novel ethyl dioxy phosphate prodrug of propofol (3) was synthesized and characterized in vitro and in vivo as safer alternative for phosphonooxymethyl prodrugs. The synthesis of 3 was achieved via vinyl and 1-chloroethyl ether intermediates, followed by addition of phosphate group. Aqueous solubility and chemical stability of 3 was determined in buffer solutions and the bioconversion of 3 to propofol was determined in vitro and in vivo. The results show that 3 greatly enhanced the aqueous solubility of propofol (solubility over 10 mg/mL) and the stability in buffer solution (t1/2=5.2+/-0.2 days at pH 7.4, r.t.) was sufficient for i.v. administration. The enzymatic hydrolysis of 3 to propofol was extremely rapid in vitro (t1/2=21+/-3s) and 3 was readily converted to propofol in vivo in rats. During bioconversion, 3 releases acetaldehyde, a less toxic compound than the formaldehyde released from the phosphonooxymethyl prodrug of propofol (Aquavan), currently undergoing clinical trials. The maximum plasma concentration of propofol, 3.0+/-0.2 microg/mL, was reached within 2.1+/-0.8 min after the i.v. administration of 3. The present study indicates that ethyl dioxy phosphate represents a potentially useful water-soluble prodrug structure suitable for i.v. administration.

Prodrugs: design and clinical applications.

Prodrugs are bioreversible derivatives of drug molecules that undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which can then exert the desired pharmacological effect. In both drug discovery and development, prodrugs have become an established tool for improving physicochemical, biopharmaceutical or pharmacokinetic properties of pharmacologically active agents. About 5-7% of drugs approved worldwide can be classified as prodrugs, and the implementation of a prodrug approach in the early stages of drug discovery is a growing trend. To illustrate the applicability of the prodrug strategy, this article describes the most common functional groups that are amenable to prodrug design, and highlights examples of prodrugs that are either launched or are undergoing human trials.

Novel cyclic phosphate prodrug approach for cytochrome P450-activated drugs containing an alcohol functionality.

PURPOSE: A cyclic phosphate prodrug of a descriptive molecule containing an alcohol functionality was designed, synthesized and characterized in vitro as a cytochrome P450 (CYP) -selective prodrug. MATERIALS AND METHODS: To achieve efficient CYP-oxidation and prodrug bioconversion, 1,3-cyclic propyl ester of phosphate was designed to have a C4-aryl substituent and synthesized using phosphorus(III) chemistry. The two-step bioconversion of the cyclic phosphate prodrug was evaluated in vitro using human liver microsomes and recombinant CYP enzymes. RESULTS: This cyclic phosphate prodrug underwent initial CYP-catalyzed oxidation and was mainly catalyzed by the CYP3A4 form. The hydroxylated product was slowly converted to a ring-opened intermediate, which subsequently transformed by beta-elimination reaction to a free phosphate. The free phosphate was further dephosphorylated by microsomal phosphatases, releasing the parent molecule with a free hydroxyl group. The cyclic phosphate was reasonably stable in buffer solutions at the pH range 1.0-9.0. CONCLUSIONS: Since CYP enzymes reside predominantly in the liver and secondarily in the small intestine, the results indicate that cyclic phosphate prodrugs represent a very feasible liver- or intestinal-targeted drug delivery strategy for drug molecules containing an alcohol functionality. This may potentially improve the efficacy and the safety profile of the alcoholic parent drugs.

Evaluation of hydroxyimine as cytochrome P450-selective prodrug structure.

Hydroxyimine derivatives of ketoprofen (1) and nabumetone (2) were synthesized and evaluated in vitro and in vivo as cytochrome P450-selective intermediate prodrug structures of ketones. 2 released nabumetone in vitro in the presence of isolated rat and human liver microsomes and in different recombinant human CYP isoforms. Bioconversion of 2 to both nabumetone and its active metabolite, 6-methoxy-2-naphthylacetic acid (6-MNA), was further confirmed in rats in vivo. Results indicate that hydroxyimine is a useful intermediate prodrug structure for ketone drugs.

An efficient strategy for the synthesis of 1-chloroethyl phosphates and phosphoramidates.

[reaction: see text] A versatile, efficient, and simple method for the preparation of various 1-chloroethyl phosphates and phosphoramidates is described. The protected chlorophosphates or phosphoramidates are synthesized to the vinyl derivative under mild conditions, followed by conversion to the chloroethylidene phosphate or phosphoramidate by dry HCl gas, resulting in good to excellent yields. 1-Chloroethyl phosphates and phosphoramidates are excellent building blocks for the synthesis of novel ethylidene-linked phosphate prodrugs.