Amide Prodrugs Research Articles

Ester and Amide Prodrugs of Ibuprofen and Naproxen: Synthesis, Anti-inflammatory Activity, and Gastrointestinal Toxicity

Ester and amide prodrugs of ibuprofen (1) and naproxen (16) were synthesized and evaluated for anti-inflammatory activity and gastrointestinal toxicity. The chemical structure of the prodrugs was varied in terms of lipophilicity and reactivity toward hydrolysis. Inhibition of acetic acid-induced writhing in mice indicated that prodrugs 7,15,19, and 20 exhibited significantly better activity (p < 0.01) than the parent compounds. The average number of ulcers formed in the gastric mucosa following oral administration of 1 and 16 and prodrugs 5, 18, 21, and 22 was determined in rats. All prodrugs, except the glycine amide 21, were significantly less irritating to the gastric mucosa than either 1 or 16.

Amine prodrugs which utilize hydroxy amide lactonization. II. A potential esterase-sensitive amide prodrug.

In an effort to develop esterase-sensitive pro-prodrugs for amines, an amide derivative of 3-(2'-acetoxy-4',6'-dimethylphenyl)-3,3- dimethylpropionic acid (4-methoxyaniline amide 8) was synthesized and its stability investigated. This esterified hydroxy amide was found under all conditions to degrade via a two-step process initiated by acetyl ester hydrolysis generating the hydroxy amide intermediate 9a. The lactonization of this intermediate 9a in the second step resulted in the formation of 4-methoxyaniline (10) and 4,4,5,7-tetramethyl-3,4-dihydrocoumarin (1a). The pro-prodrug 8 was observed to possess the following half-lives at 37 degrees C under various conditions: 4030 min in phosphate buffer (50 mM, mu = 0.15) fixed to pH 7.4, 11.9 min in the same buffer containing a porcine liver esterase, 53.7 min in plasma, and 475 min in plasma containing diisopropylfluorophosphate. These results suggest that in a biological milieu the ester hydrolysis will occur by the enzymic hydrolysis rather than the chemical hydrolysis and that the enzymic hydrolysis of 8 in plasma is due, in part, to the action of serine-dependent esterases.

Amine prodrugs which utilize hydroxy amide lactonization. I. A potential redox-sensitive amide prodrug.

Several amides of 3-(3',6'-dioxo-2',4'-dimethylcyclohexa-1',4'-diene)-3,3- dimethylpropionic acid (2) have been synthesized and tested as model redox-sensitive pro-prodrugs of amines. The reduction of these model pro-prodrugs generated hydroxy amide intermediates 4a-4h, the lactonization of which resulted in amine release. The rates of lactonization of 4a-4h were investigated at pH 7.4 and 37 degrees C. The half-lives for appearance of the product lactone 1a from these intermediates were found to range from 1.4 to 3.4 min. With such rapid lactonization rates, it is believed that reduction will be the rate-limiting step in the two-step conversion of the pro-prodrug to the amine.

Sequentially labile water-soluble prodrugs of alprazolam.

A 1,4-benzodiazepine analogue alprazolam (1) undergoes ring-opening hydrolysis under acidic conditions to form a triazolobenzophenone (2). At a neutral pH, 2 rapidly and quantitatively cyclizes back to 1. This facile reversible reaction was utilized in developing water-soluble prodrugs of 1 in which the "solubility anchoring" acyl moieties are formyl, acetyl, succinyl, glycyl, leucyl, and gamma-aminobutyryl groups. These compounds were prepared directly from 2 and corresponding acids through DCC coupling in a 1:1 mixture of H2O and THF. They should be stable in aqueous media at room temperature. Promoieties used should be nontoxic at an intended dose level. In vitro human serum hydrolysis study showed that only glycyl and leucyl amides were able to regenerate 1 within a reasonable period of time. Ex vivo competitive receptor binding assay in mice with [3H]flunitrazepam indicated that leucyl amide prodrug should be able to produce a rapid onset of the intrinsic central nervous system activity of 1 when parenterally administered. For all compounds studied, the final outcome of the biological response appears to be kinetically controlled, rather than by an unfavorable equilibrium, particularly by the first step in which the amide bond is hydrolyzed in vivo.