Carbonate Ester Prodrugs of Salicylic Acid

Dittert, Lewis W.; Caldwell, Henry C.; Ellison, Theodore; Irwin, George M.; Rivard, Donald E.; Swintosky, Joseph V.

doi:10.1002/jps.2600570523

Cited by 31 publications

(5 citation statements)

References 13 publications

(1 reference statement)

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“…The effect of structure on the enzymatic half-life was investigated in a number of prodrug and soft drug series. ,,,,,− An attempt by Charton for quantitative lability prediction in a number of individual prodrug series, − using steric and polarizability parameters, resulted in some success, but failed to establish any relationship of general validity. Altomare and co-workers 36 and Testa and co-workers 30,39,40 also attempted to establish quantitative structure−metabolism relationships limited to the ester-containing prodrug series they examined.…”

Section: Introductionmentioning

confidence: 99%

Quantitative Structure−Metabolism Relationships: Steric and Nonsteric Effects in the Enzymatic Hydrolysis of Noncongener Carboxylic Esters

Buchwald

Bodor

1999

J. Med. Chem.

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An attempt to quantitatively describe human blood in vitro hydrolysis data for more than 80 compounds belonging to seven different noncongener series of ester-containing drugs is presented. A parameter not yet explored in pharmaceutical studies, the inaccessible solid angle Omega(h), calculated around different atoms was used as a measure of steric hindrance, and the steric hindrance around the carbonyl sp(2) oxygen (Omega(h)(O=)) proved the most relevant parameter. The obtained final equation, log t(1/2) = -3.805 + 0.172Omega(h)(O=) - 10.146q(C=) + 0.112QLogP, also includes the AM1-calculated charge on the carbonyl carbon (q(C=)) and a calculated log octanol-water partition coefficient (QLogP) as parameters and accounts for 80% of the variability in the log half-lives of 67 compounds. A number of structures are still mispredicted, but the equation agrees very well with a recently proposed mechanism for hydrolysis by carboxylesterases. The model, with a predictive power tested here on three unrelated structures, should be useful in estimating approximate rates of hydrolysis for prodrug or soft drug candidates ahead of their synthesis.

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Section: Introductionmentioning

confidence: 99%

Quantitative Structure−Metabolism Relationships: Steric and Nonsteric Effects in the Enzymatic Hydrolysis of Noncongener Carboxylic Esters

Buchwald

Bodor

1999

J. Med. Chem.

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“…N-arlyhydrazone derivatives of mefenamic acid (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21) were evaluated for analgesic activity (fig 4). Except compounds 13, 16, 17 and 21, all of them induced significant analgesic activity and among them 7 compounds significantly showed higher inhibitory effect on the writhing response in comparison to mefenamic acid as follow: (10, 71.1%), (11, 58.5%), (14, 46.7%), (15, 42.4%), (18, 67.9%), (19, 93.7%), (20, 50.9%), mefenamic acid (25.6%).…”

Section: Resultsmentioning

confidence: 99%

“…For nonsteroidal anti-inflammatory carboxylic acids such as mefenamic acid or N-(7-chloro-4quinolyl)anthranilic acid [11], glyceryl esters are claimed to be less irritating. Alternatively, the ulcerogenicity of indomethacin derivatives was reduced by formation of the ester with glycolic acid [12] or the peptide with serine [13]. Another indomethacin-related anti-inflammatory drug, sulindac, is an inactive sulfoxide and becomes only activated after absorption and reduction into the corresponding sulfide.…”

Section: Flufenamic Acidmentioning

confidence: 99%

Anthranylic Acid

2004

Encyclopedic Dictionary of Genetics, Genomics and Proteomics

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Anthranylic acid derivatives are direct structural analogs of salicylic acid derivatives. They possess analgesic, anti-inflammatory, and antipyretic activity. They are similar to pyrazolones in terms of analgesic and antipyretic activity, yet they exceed the anti-inflammatory activity of salicylates. The mechanism of action of this series of nonsteroid, anti-inflammatory analgesics is not conclusively known. One of the early advances in the search for nonnarcotic analgesics was centered in the N-arylanthranilic acids. The outstanding characteristic of mefenamic acid is primarily anti-inflammatory , and secondarily, some possess analgesic properties.

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“…5-(4-Imidazolyl)salicylic Acid (9). 4-(4-Anisyl)imidazole (1.6 g)13 was refluxed in 48% HBr (15 mL) for 1.5 h. The cooled reaction mixture was filtered and the solid dropped into ice-cold aqueous NaHC03.…”

Section: Methodsmentioning

confidence: 99%

Synthesis and analgesic-antiinflammatory activity of some 4- and 5-substituted heteroarylsalicylic acids

Jones¹,

Mw²,

Rb³

et al. 1978

J. Med. Chem.

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We have made a series of 4- and 5-aryl- and 4- and 5-heteroarylsalicylic acid derivatives with the objective of reducing gastric irritation and increasing potency. Here we describe a series of 4- and 5-heterocyclic salicylic acids and their antiinflammatory-analgesic potencies measured in comparison to aspirin. An improvement of the therapeutic index over aspirin of 100 was achieved; however, the heterocyclic salicylic acids lacked antipyretic activity. Some physicochemical parameters which may bear on the antiinflammatory activity of these compounds are discussed.

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Carbonate Ester Prodrugs of Salicylic Acid

Cited by 31 publications

References 13 publications

Quantitative Structure−Metabolism Relationships: Steric and Nonsteric Effects in the Enzymatic Hydrolysis of Noncongener Carboxylic Esters

Quantitative Structure−Metabolism Relationships: Steric and Nonsteric Effects in the Enzymatic Hydrolysis of Noncongener Carboxylic Esters

Anthranylic Acid

Synthesis and analgesic-antiinflammatory activity of some 4- and 5-substituted heteroarylsalicylic acids

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