Synthesis, characterization and in vitro hydrolysis of a gemfibrozil-nicotinic acid codrug for improvement of lipid profile.

Combination therapy of fibrates and nicotinic acid has been reported to be synergistic. Herein, we describe a covalent codrug of gemfibrozil (GEM) and nicotinic acid (NA) that was synthesized and characterized by (1)H NMR, (13)C NMR, FT-IR, MS analysis and elemental analysis. A validated HPLC method was developed that allows for the accurate quantitative determination of the codrug and its hydrolytic products that are formed during the in vitro chemical and enzymatic hydrolysis. The physico-chemical properties of codrug were improved compared to its parent drugs in term of water solubility and partition coefficient. The kinetics of hydrolysis of the codrug was studied using accelerated hydrolysis experiments at high temperatures in aqueous phosphate buffer solution in pH 1.2, 6.8 and 7.4. Using the Arrhenius equation, the extrapolated half-life at 37°C were 289 days at pH 1.2 for the codrug and 130 and 20,315 days at pH 6.8 for the codrug and gemfibrozil 2-hydroxyethyl ester (GHEE), respectively. The shortest half-lives were at pH 7.4; 42 days for the codrug and 5837 days for GHEE, respectively. The hydrolysis of the latter was studied, alone, at 80°C and pH 1.2 and compared to its hydrolysis when it is produced from the codrug using similar conditions. The k(obs) was found in both cases to be 1.60×10(-3)h(-1). The half-lives in plasma were 35.24 min and 26.75 h for the codrug and GHEE, respectively. With regard to liver homogenate, the hydrolysis half-lives were 1.96 min and 48.13 min for the codrug and GHEE, respectively. It can be expected that in vivo, the codrug will liberate NA immediately in plasma then GEM will be liberated from its 2-hydroxyethyl ester in the liver.

The excitation-contraction coupling on C2C12 skeletal muscle myotubes was modulated by NO-donor ester of gemfibrozil.

The excitation-contraction coupling in skeletal muscle is modulated by nitric oxide via redox status modification of ryanodine receptor on sarcoplasmic reticulum during events that lead to muscle contraction. We have synthesized a derivative of antilipidemic drug, gemfibrozil, in which a NO-donor furoxan moiety is joined to the fibrate by an ester linkage. Aim of the present study was to determine if the NO released from the above compound is capable of influencing the NO-sensible E-C coupling steps in skeletal muscle and if this effect could be potentially utilised for physiopathological studies and pharmaceutical applications. To obtain this goal we decided to study some of the excitation-contraction mechanisms in the presence of NO-releasing derivative of gemfibrozil in skeletal muscle C2C12 cell line.

Synthesis of fenoprofen and gemfibrozil styrene-maleic acid copolymer conjugates.

Two types of polymer-drug conjugates were synthesized starting from styrene-maleic acid anhydride copolymer (SMA). Fenoprofen and gemfibrozil were chosen as model drugs because of their short plasma half lives. Both drugs were first converted to their 2-aminoethylamides, which possess free amino groups capable of reacting with SMA anhydride rings. By modifying the degree and type of substitution, lipophilic and hydrophilic conjugates were obtained. Drug loading in the conjugates was between 17 and 47%.

Thiourea-based gemfibrozil analogues as HDL-elevating agents.

A series of gemfibrozil analogues with a thiourea moiety embedded in the side chain was prepared and evaluated as HDL-elevating agents. Derivatives 8b, 9b, 9c, and 9d were found to be approximately as effective as gemfibrozil (1) for HDL cholesterol elevation.

Synthesis and antiplatelet activity of gemfibrozil chiral analogues.

The chiral analogues of gemfibrozil 5-(2,5-dimethylphenoxy)-2-methylpentanoic acid and 5-(2,5-dimethylphenoxy)-2-ethylpentanoic acid were synthesized in optically active form using (S)-4-(1-methylethyl)-2-oxazolidinone as chiral auxiliary. All compounds inhibit human platelet aggregation. From these data, one can surmise that all tested compounds and gemfibrozil act at the platelet level with different mechanism than that of ASA, even if with a different potency.

Macromolecular prodrugs. VIII. Synthesis of polymer-gemfibrozil conjugates.

Gemfibrozil is covalently linked to two similar polymers: poly[alpha,beta-(N-2-hydroxyethyl-DL-aspartamide)] and poly[alpha,beta-(N-3-hydroxypropyl-DL-aspartamide)]. The synthesised polymer drug conjugates differ in average molecular mass, type of covalent bonding, length of spacer, drug-loading and solubility.