Alkaline Hydrolysis of Some Carbamic Acid Esters.

Christenson, I; Persson, Kaj; Thorkilsen, B.; Halvarson, Hans; Nilsson, Lennart

doi:10.3891/acta.chem.scand.18-0904

Cited by 57 publications

(29 citation statements)

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“…With the exception of the cyclohexylmethyl ( 9 ) and 1-adamantyl ( 10 ) derivatives, substitution of the N -cyclohexyl ( 1 ) group with an alkyl ( 3 – 6 ), cycloalkyl ( 7 , 8 ) or arylalkyl ( 11 , 12 , 14-20 ) group did not significantly influence t 1/2 values, which showed an averaged value of 39.2 min (n = 18). These results are consistent with the fact that the chemical stability of O -aryl carbamates is pH-dependent, with hydrolysis rates increasing with hydroxide ion concentration as a consequence of two concurring mechanisms, a common B AC 2 and an elimination-addition one (E1cB) [39,40,41,42]. …”

Section: Resultssupporting

confidence: 85%

Biphenyl-3-yl alkylcarbamates as fatty acid amide hydrolase (FAAH) inhibitors: Steric effects of N-alkyl chain on rat plasma and liver stability

Vacondio

Lodola

Carmi

et al. 2011

European Journal of Medicinal Chemistry

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Secondary alkylcarbamic acid biphenyl-3-yl esters are a class of Fatty Acid Amide Hydrolase (FAAH) inhibitors, which include the reference compounds URB597 and URB694. Given the intrinsic reactivity of the carbamate group, the in vivo potency of these molecules in rats is strongly affected by their hydrolysis in plasma or hepatic metabolism. In the present study, in vitro chemical and metabolic stability assays (rat plasma and rat liver S9 fraction) were used to investigate the structure-property relationships (SPRs) for a focused series of title compounds, where lipophilicity and steric hindrance of the carbamate N-substituent had been modulated. The resulting degradation rates indicate that a secondary or tertiary alkyl group at the carbamate nitrogen atom increases hydrolytic stability towards rat plasma esterases. The calculated solvent accessible surface area (SASA) of the carbamate fragment was employed to describe the differences observed in rate constants of hydrolysis in rat plasma (log kplasma), suggesting that stability in plasma increases if the substituent exerts a shielding effect on the carbamate carbonyl. Stability in rat liver S9 fraction is increased when a tertiary carbon is bound to the carbamate nitrogen atom, while other steric effects showed complex relationships with degradation rates. The SPRs here described may be applied at the pharmacokinetic optimization of other classes of carbamate FAAH inhibitors.

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Section: Resultssupporting

confidence: 85%

Biphenyl-3-yl alkylcarbamates as fatty acid amide hydrolase (FAAH) inhibitors: Steric effects of N-alkyl chain on rat plasma and liver stability

Vacondio

Lodola

Carmi

et al. 2011

European Journal of Medicinal Chemistry

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“…Simple O-alkyl carbamates are extraordinarily stable toward O-acyl-bond hydrolysis, showing half-lives of many years at physiological pH (7); for example, hydroxide-catalyzed hydrolysis of phenyl urethane proceeds at ∼0.1 M −1 ·h −1 (8), which corresponds to a halflife of over a millennium for hydroxide-catalyzed cleavage at pH 7.4. However, cleavage of the O-alkyl bond of a carbamate by an alternative route results in formation of a carbamic acid and subsequent rapid generation of the amine-containing moiety.…”

Section: Resultsmentioning

confidence: 99%

Predictable and tunable half-life extension of therapeutic agents by controlled chemical release from macromolecular conjugates

Santi

Schneider

Reid

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

177

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Conjugation to macromolecular carriers is a proven strategy for improving the pharmacokinetics of drugs, with many stable polyethylene glycol conjugates having reached the market. Stable conjugates suffer several limitations: loss of drug potency due to conjugation, confining the drug to the extracellular space, and the requirement for a circulating conjugate. Current research is directed toward overcoming such limitations through releasable conjugates in which the drug is covalently linked to the carrier through a cleavable linker. Satisfactory linkers that provide predictable cleavage rates tunable over a wide time range that are useful for both circulating and noncirculating conjugates are not yet available. We describe such conjugation linkers on the basis of a nonenzymatic β-elimination reaction with preprogrammed, highly tunable cleavage rates. A set of modular linkers is described that bears a succinimidyl carbonate group for attachment to an amine-containing drug or prodrug, an azido group for conjugation to the carrier, and a tunable modulator that controls the rate of β-eliminative cleavage. The linkers provide predictable, tunable release rates of ligands from macromolecular conjugates both in vitro and in vivo, with half-lives spanning from a range of hours to >1 y at physiological pH. A circulating PEG conjugate achieved a 56-fold half-life extension of the 39-aa peptide exenatide in rats, and a noncirculating s.c. hydrogel conjugate achieved a 150-fold extension. Using slow-cleaving linkers, the latter may provide a generic format for once-a-month dosage forms of potent drugs. The releasable linkers provide additional benefits that include lowering C max and pharmacokinetic coordination of drug combinations. metronomic chemotherapy | implant M any drugs and drug candidates are suboptimal or ineffective because of a short duration of action. For example, peptides and proteins with promising therapeutic value often have serum half-lives of only minutes to hours. One solution to this problem involves conjugation to carriers such as polyethylene glycol (PEG), the Fc portion of IgG, serum albumin, and other longlived macromolecules. The large carriers retard kidney filtration and hence increase plasma half-life of the attached drug. Much success has been realized thus far with PEG as the macromolecular carrier. PEG is nontoxic and nonimmunogenic, and the plasma half-life is a function of hydrodynamic size. Conjugation of drugs to PEG with molecular mass ∼40 kDa has been successfully used with peptides, nucleic acids, and small molecules and can afford half-lives of up to ∼7 d in humans; as of 2011, 10 PEGylated peptide-based drugs were approved by the Food and Drug Administration (FDA) and ∼40 were in clinical trials (1, 2).All of the currently marketed PEG-protein conjugates are permanently PEGylated. Attachment of large PEG moieties often reduces activity of the drug, and higher concentrations of conjugate are necessary to achieve the required biological activity. A further limitation is that permanen...

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“…Pyrethroids, organophosphates and carbamates degrade via hydrophilic attack of the carboxylic and carbamic ester linkages [11-13]. DDT undergoes alkaline dechlorination to yield DDE [14].…”

Section: Introductionmentioning

confidence: 99%

Degradation of insecticides used for indoor spraying in malaria control and possible solutions

Sibanda

Focke

Labuschagne

et al. 2011

Malar J

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BackgroundThe insecticide dichloro-diphenyl-trichloroethane (DDT) is widely used in indoor residual spraying (IRS) for malaria control owing to its longer residual efficacy in the field compared to other World Health Organization (WHO) alternatives. Suitable stabilization to render these alternative insecticides longer lasting could provide a less controversial and more acceptable and effective alternative insecticide formulations than DDT.MethodsThis study sought to investigate the reasons behind the often reported longer lasting behaviour of DDT by exposing all the WHO approved insecticides to high temperature, high humidity and ultra-violet light. Interactions between the insecticides and some mineral powders in the presence of an aqueous medium were also tested. Simple insecticidal paints were made using slurries of these mineral powders whilst some insecticides were dispersed into a conventional acrylic paint binder. These formulations were then spray painted on neat and manure coated mud plaques, representative of the material typically used in rural mud houses, at twice the upper limit of the WHO recommended dosage range. DDT was applied directly onto mud plaques at four times the WHO recommended concentration and on manure plaques at twice WHO recommended concentration. All plaques were subjected to accelerated ageing conditions of 40°C and a relative humidity of 90%.ResultsThe pyrethroids insecticides outperformed the carbamates and DDT in the accelerated ageing tests. Thus UV exposure, high temperature oxidation and high humidity per se were ruled out as the main causes of failure of the alternative insecticides. Gas chromatography (GC) spectrograms showed that phosphogypsum stabilised the insecticides the most against alkaline degradation (i.e., hydrolysis). Bioassay testing showed that the period of efficacy of some of these formulations was comparable to that of DDT when sprayed on mud surfaces or cattle manure coated surfaces.ConclusionsBioassay experiments indicated that incorporating insecticides into a conventional paint binder or adsorbing them onto phosphogypsum can provide for extended effective life spans that compare favourably with DDT's performance under accelerated ageing conditions. Best results were obtained with propoxur in standard acrylic emulsion paint. Similarly, insecticides adsorbed on phosphogypsum and sprayed on cattle manure coated surfaces provided superior lifespans compared with DDT sprayed directly on a similar surface.

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Alkaline Hydrolysis of Some Carbamic Acid Esters.

Cited by 57 publications

References 0 publications

Biphenyl-3-yl alkylcarbamates as fatty acid amide hydrolase (FAAH) inhibitors: Steric effects of N-alkyl chain on rat plasma and liver stability

Biphenyl-3-yl alkylcarbamates as fatty acid amide hydrolase (FAAH) inhibitors: Steric effects of N-alkyl chain on rat plasma and liver stability

Predictable and tunable half-life extension of therapeutic agents by controlled chemical release from macromolecular conjugates

Degradation of insecticides used for indoor spraying in malaria control and possible solutions

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