Novel polyoxyethylene esters of ketoprofen (1a–e), naproxen (2a–e) and diclofenac (3a–e) were synthesized and evaluated as potential dermal prodrugs of naproxen, ketoprofen and diclofenac. These esters were obtained by coupling these drugs with polyoxyethylene glycols by a succinic acid spacer. The aqueous solubilities, lipophilicities and hydrolysis rates of esters 1a–e, 2a–e and 3a–e were determined in a buffered solution and in porcine esterase. The permeation of these prodrugs through excised human skin was studied in vitro. Furthermore we investigated the in vivo topical anti-inflammatory activity of esters 1d, 2e and 3e, which showed the best in vitro profile, evaluating the ability of these compounds to inhibit methyl nicotinate (MN)-induced skin erythema on healthy human volunteers. Esters 1a–e, 2a–e and 3a–e showed good water stability and rapid enzymatic cleavage and their hydrolysis rates, both chemical and enzymatic, were not significantly affected by the length of the polyoxyethylenic chain used as promoiety. Concerning in vitro percutaneous absorption studies, only esters 1d–e, 2d–e and 3c–e showed an increased flux through stratum corneum and epidermis membranes compared to their respective parent drugs. In vivo results showed an interesting delayed and sustained activity of esters 1d and 3e compared to the parent drugs. In conclusion polyoxyethylene glycols could prove to be suitable promoieties for ketoprofen, naproxen and diclofenac design since esters 1d–e, 2d–e and 3c–e showed some requirements (chemical stability, enzymatic lability and an increased skin permeation) needed to obtain successful dermal prodrugs. Furthermore, was observed an appreciable and sustained in vivo topical anti-inflammatory activity of esters 1d and 3e, compared to the parent drugs, using MN-induced erythema in human volunteers as inflammation model.

Seventeen (un)substituted N-[4-(propyl)cyclohexyl]-amides (6a–h, 7a–h and 8) were synthesized and tested as anti-inflammatory and analgesic agents. The substituents on the aromatic ring were chosen in order to study the influence of electron-withdrawing or electron-donating residues, that change the electronic density on the aromatic moiety. The pharmacological results allow drawing some preliminary considerations on structure–activity relationships.

The aim of the present study was to investigate whether the chirality and type of substitution at position 3 of the dihydropyridine ring influences the pattern of voltage-gated Ca2+ channel blockade. For this purpose, the effect of R- and S-enantiomers of manidipine and nitrendipine, separated by chiral High-Pressure-Liquid-Chromatography columns, were investigated by fura-2 microfluorimetry during the plateau phase of the intracellular Ca2+ ([Ca2+]i) increase induced by 55 mM K+ and by patch-clamp recording of Ca2+ channel activity in GH3 cells. R- and S-enantiomers of both nitrendipine and manidipine produced a [Ca2+]i decay of the K+-induced plateau phase that followed a biexponential pattern with a `fast' and a `slow' phase. The S-configuration of both nitrendipine and manidipine produced a larger [Ca2+]i decrease during the `fast phase', and a faster and smaller [Ca2+]i decrease in the `slow phase' than did the R-enantiomers. The S- and R-enantiomers of manidipine, which possess a longer and more lipophilic side chain at position 3 of the dihydropyridine ring, induced a slower [Ca2+]i decrease than that observed with the respective nitrendipine enantiomers. Accordingly, patch-clamp experiments revealed that the S-enantiomers of both dihydropyridines displayed a faster onset of action and produced a greater blockade than the R-enantiomers. These results suggest that the enantiomeric configuration and a small side chain at position 3 of the dihydropyridine ring are factors in the chemical structure which influence the pattern of blockade of voltage-sensitive Ca2+ channels.

Nipecotic acid (1), one of the most potent in vitro inhibitors of neuronal and glial gamma-amino butyric acid (GABA) uptake, is inactive as an anticonvulsant when administered systemically. To obtain in vivo active prodrugs of (1), we synthesized four new nipecotic acid esters (3-6), which were obtained by chemical conjugation with glucose, galactose, and tyrosine. These compounds were assayed to evaluate their in vitro chemical and enzymatic hydrolysis. In addition, their anticonvulsant activity was evaluated in vivo in Diluted Brown Agouti (DBA)/2 mice, an excellent animal model for the study of new anticonvulsant drugs. Esters (3-6) appeared stable, at various temperatures, in a pH 7.4 buffered solution and showed susceptibility to undergoing in vitro enzymatic hydrolysis. Intraperitoneally injected nipecotic acid (1) and esters (3-5) did not protect mice against audiogenic seizures; conversely, nipecotic tyrosine ester (6) showed a significant dose-dependent anticonvulsant activity. The in vivo protective activity of the ester (6) and the inefficiency of nipecotic acid (1) in the same experimental conditions suggest that this ester prodrug could be actively transported intact across the blood-brain barrier, beyond which it could be hydrolyzed.

Two series of N-[4-(alkyl)cyclohexyl]-substituted benzamides, i.e. a series of N-[4-(tert-butyl)cyclohexyl]-substituted benzamides and a series of N-[4-(ethyl)cyclohexyl]-substituted benzamides, were synthesised and evaluated for their anti-inflammatory and analgesic potencies, and gastrointestinal irritation liability.

Two series of 1-methyl-4-(N-aroyl)-piperidinamides were synthesized and evaluated for their anti-inflammatory and analgesic properties, as well as for their gastrointestinal irritation liability. A non-aromatic derivative, 1-methyl-4-(N-cyclohexanoyl)-piperidinamide, was synthesized and evaluated in order to obtain a more exhaustive knowledge of the structure-activity relationship.

Indomethacin terpenoids' esters (1-4) were synthesized and assessed both in vitro and in vivo as indomethacin dermal prodrugs. Esters 1-4 showed high lipophilicity, poor water solubility, good stability in hydro-alcoholic medium (ethanol/water 1:1) and rapid enzymatic cleavage. Results from in vitro percutaneous absorption studies showed that esters 1 and 2 slightly increased the cumulative uptake of indomethacin through excised human skin compared with the parent drug. In vivo results, using methyl nicotinate (MN) induced erythema as an inflammatory model in human volunteers, showed an interesting delayed and sustained activity of ester 1 compared with the parent drugs. (C) 1997 Elsevier Science B.V.

4-(3,4-Dihydro-2,4-dioxo-2H-1,3-benzoxazin-3-yl)-butyric acid (7) and its ester 6, two potential gamma-aminobutyric acid (GABA) prodrugs, were synthesized and studied to determine their stability in aqueous buffer and their susceptibility to undergo enzymatic hydrolysis in vitro (mouse plasma). Both compounds were fairly stable in aqueous media, (t1/2 = 68.2 h and 25.7 h, respectively). The 3,4-dihydro-2,4-dioxo-2H-1,3-benzoxazine ring underwent enzymatic hydrolysis (t1/2 = 5.8 h) in compound 7, whereas in compound 6 it seemed not to be opened by mouse plasma esterases within the observation time (3h). Both compounds were tested for their anticonvulsant activity in pentetrazole (PTZ) treated mice, and showed significant activity. Compound 7, administered as sodium salt 8, was active at relatively low doses and can be considered a very interesting GABA prodrug.

A series of N-Aroyl-cyclohexyl- and cyclohexenylamides 3- or 4-methylsubstituted were synthesized and evaluated for their anti-inflammatory and analgesic potencies, and gastrointestinal irritation liability. One compound, N-benzoyl-4-methyl-cyclohexylamide 6a, possessed an anti-inflammatory activity comparable to that of indomethacin.

Some (un)substituted imidazo[2,1-b]benzothiazole carboxylic or acetic acids and some related compounds, i.e. imidazo[2,1-b]naphthol[2,1-d]thiazole, 4H-imidazo[2,1-c][1,4]benzothiazine, 4,5-dihydroimidazo[2,1-d][1,5]benzothiazepine carboxylic and acetic acids were synthesized and tested in vivo in order to study the structure-activity relationships (SAR) of their antiinflammatory and analgesic activities. Pharmacological assays confirmed the interest of this class of compounds as potential antiinflammatory and analgesic drugs with low side effects.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The pharmacokinetic and pharmacodynamic profile of triethylene glycol indomethacin ester (TIE), an indomethacin oral prodrug, was investigated after oral administration to rats (indomethacin 5 mg/kg; TIE 20 mg/kg). In vitro enzymatic hydrolysis studies using rat plasma showed that TIE was quantitatively reconverted into indomethacin at a very fast rate. After TIE oral dosing, indomethacin mean peak plasma concentration was lower than after indomethacin administration (16.30 and 30.25 μg/ml, respectively) and mean time to the peak plasma concentration was slightly higher than that observed after indomethacin (4 and 3 h, respectively). TIE oral administration to rats gave lower but relatively constant indomethacin plasma levels for the observation period (24 h). The results from the biological response time course of carrageenan-induced paw edema after indomethacin and TIE administration showed that both drug and prodrug were able to inhibit the inflammatory process over the observation period (7 h). Furthermore, the paw/blood concentration ratio of indomethacin 3 h after carrageenan injection was similar after oral administration of indomethacin or TIE. TIE pharmacokinetic profile could be attributed to a different absorption of the prodrug in the gastrointestinal tract compared to indomethacin.

Indomethacin polyoxyethylene esters (1–5) were synthesized and assessed both in vitro and in vivo for their usefulness as indomethacin dermal prodrugs. Esters 1–5 showed good water stability and rapid enzymatic cleavage and their hydrolysis rates, both chemical and enzymatic, were not significantly affected by the lengthen of the polyoxyethylenic chain used as promoiety. Results from in vitro percutaneous absorption studies showed that only esters 4 and 5 significantly increased indomethacin cumulative amount penetrated through excised human skin compared to the parent drug. In vivo topical anti-inflammatory activity, using methyl nicotinate (MN) induced erythema as inflammation model in human volunteers, was investigated for ester 5, which showed the best in vitro results. In vivo results showed an interesting delayed and sustained activity of ester 5 compared to the parent drug.

We have prepared twelve imidazo[2,1-b]benzothiazole carboxylic and acetic acids by reaction of substituted 2-aminobenzothiazoles with ethyl bromopyruvate and 4-chloroacetoacetate, respectively. The acids, obtained from esters by hydrolysis, were tested for their antiinflammatory, analgesic and ulcerogenic activities.