Ester Prodrugs of Ketoprofen: Synthesis, Hydrolysis Kinetics and Pharmacological Evaluation

Dhokchawle, B. V.; Tauro, Savita; Bhandari, Anil

doi:10.1055/s-0035-1548908

Cited by 8 publications

(11 citation statements)

References 19 publications

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“…In any case, with the exception of the amino acid derivatives (7,8), the derivatives are more lipophilic than the phenolic compound 1. This is in line with expectations, as with other ester prodrugs this tendency has already been demonstrated [17]. The tested azecine derivatives have octanol/ water partition coefficients between 0.95 and 4.59.…”

Section: Discussionsupporting

confidence: 92%

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In Vitro Studies on Physiological and Chemical Stability of New LE404-Derivatives with Extended Half-Life

Zergiebel

Seeling

2018

Drug Res (Stuttg)

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Dibenzoazecines are a class of potential neuroleptics with high affinity to dopamine and serotonin receptors. The efficacy and high therapeutic range has already been demonstrated in vivo with the lead structure 7-methyl-5,6,7,8,9,14-hexahydrodibenzo[d,g]azecin-3-ol (LE404: ) and selected derivatives. There is a variety of new synthesized structurally different dibenzoazecine derivatives with the aim to improve pharmacokinetic parameters, all of which contain the lead structure LE404: . For a multitude of these substances is still a lack of information, inclusive of stability, physicochemical parameters, pharmacokinetics and metabolism. Therefore, the present study investigated the stability properties of 17 new azecine derivatives, including esterase cleavage, stability in simulated gastrointestinal fluid, stability at different pH-values and determination of octanol/water-partition coefficients. These findings, in correlation to the properties and efficacy of the already in vivo tested substances, will be useful for safety and efficacy in further in vivo tests.

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Section: Discussionsupporting

confidence: 92%

“…The carbamates (13, 14, 15), the propinyl derivatives (17,18) and the sulfonic acid ester 12 showed no pH-dependent instability over the test period of 6 h. For all other derivatives, the percent decrease within 6 h under basic conditions is illustrated in ▶Fig. 1.…”

Section: Ph Dependent Stabilitymentioning

confidence: 95%

In Vitro Studies on Physiological and Chemical Stability of New LE404-Derivatives with Extended Half-Life

Zergiebel

Seeling

2018

Drug Res (Stuttg)

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“…Investigations had shown that synthesis of the prodrug valaciclovir (valin esterification of aciclovir) results in significant higher plasma levels as aciclovir [28]. This esterification is possible by dicyclohexyl carbodiimide (DCC) coupling [29].…”

Section: Discussionmentioning

confidence: 99%

Synthesis and Characterization of new Azecine-Derivatives as Potential Neuroleptics

et al. 2017

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Dibenzo- and benzindolo-azecines represent a class of potential neuroleptics. To characterize the effectiveness at the dopamine and 5-HT-receptor representative structures were synthesized and tested by radio ligand binding studies, in vivo and in vitro studies.Neuroleptic potency and the risk of side effects of the prodrug 7-methyl-5,6,7,8,9,14-hexahydrodibenzo[d,g]azecin-3-yl isobutyrate, an ester derivative of the most promising azecine 7-methyl-5,6,7,8,9,14-hexahydrodibenzo[d,g]azecin-3-ol (LE404), was tested in vivo concerning conditioned avoidance response inhibition, locomotor activity and triggering of catalepsy vs. haloperidol as a reference. Also ester hydrolysis was examined using porcine liver esterase to thereby obtain an indication of the stability of the prodrug in vivo. An HPLC method was developed for purity control and determination of octanol/water-distribution coefficients.It has been shown that the tested substances in their efficacy are comparable to haloperidol and risperidone, but the therapeutic index in most cases is larger. Esterification as a prodrug principle leads to significantly prolonged effectiveness.

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“…Ketoprofen is practically insoluble in water; the formation of salts contributes to the solubility of ketoprofen [6]. The esterification reaction is used for the synthesis of ketoprofen esters, which are investigated as prodrugs [13]. The formation of esters with different substances (menthol, thymol, eugenol, etc.)…”

Section: Introductionmentioning

confidence: 99%

“…The formation of esters with different substances (menthol, thymol, eugenol, etc.) affects the analgesic efficacy and ulcerogenic potential not only of ketoprofen [13], but also of other derivatives of propionic acid, such as ibuprofen [14,15]. Experiments on experimental animals have shown that esters of ketoprofen with polyethylene glycols can be considered as promising prodrugs, because when they were administered intramuscularly their analgesic efficacy and anti-inflammatory effect were better than effectiveness of ketoprofen [16].…”

Section: Introductionmentioning

confidence: 99%

Substantiation of an approach to determination of ketoprofen macrogol 400 esters

Bezuglaya

Zinchenko

Lyapunov

et al. 2021

SR: PS

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The aim. The work is concerned with the substantiation of the approach to the identification and quantitative determination of ketoprofen macrogol 400 esters. Materials and methods. Ketoprofen, macrogol 400, ketoprofen macrogol 400 ester (KM400E), as well as model cream-gels were studied by the following methods: absorption spectrophotometry ultraviolet (UV) and visible, high-performance liquid chromatography (HPLC), gas chromatography (GC), GC / mass spectrometry, nuclear magnetic resonance (NMR) spectrometry and thermogravimetry. Results. It was found by GC and GC / mass spectrometry that the average molecular mass (Mr) of the test macrogol 400 is 383.50 and it contains oligomers with molecular masses from 150.17 to 546.65. KM400E, which is a mixture of esters of ketoprofen with macrogol oligomers, was synthesized. The formed esters were characterized by 1H NMR spectra. It was shown that the ratio of the average molecular mass of KM400E, calculated for monoesters, and the molecular mass of ketoprofen corresponds to the ratio of specific absorbances of solutions of ketoprofen and solutions of KM400E, this fact indicated the formation of monoesters. Taking into account the risk of variability of the fractional composition of macrogol 400 in different batches, it is advisable to quantify KM400E using ketoprofen reference standard (RS) and not KM400E RS. Using HPLC with diode array detection the peak of KM400E should be identified by the UV absorption spectrum with λmax≈255 nm, which is characteristic for ketoprofen, and the relative retention time (RRt) of the peak; KM400E should be quantified by the content of ketoprofen in this impurity. During storage of model cream-gels the content of KM400E impurity is significantly lower than the content of ketoprofen propylene glycol ester (mixture of isomers). Conclusions. The approach to the identification and quantitative determination of KM400E is substantiated. The analytical procedure for determination of KM400E impurity by HPLC with a diode array detection using ketoprofen RS was developed. Correctness of the procedure was proved by the results of the validation studies.

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Ester Prodrugs of Ketoprofen: Synthesis, Hydrolysis Kinetics and Pharmacological Evaluation

Cited by 8 publications

References 19 publications

In Vitro Studies on Physiological and Chemical Stability of New LE404-Derivatives with Extended Half-Life

In Vitro Studies on Physiological and Chemical Stability of New LE404-Derivatives with Extended Half-Life

Synthesis and Characterization of new Azecine-Derivatives as Potential Neuroleptics

Substantiation of an approach to determination of ketoprofen macrogol 400 esters

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