A Double-Peaked Quantitive Structure-Activity Relationship (Qsar) in A Series of Paracetamol Derivatives

Dearden, John C.; O'Hara, J.H.; Townend, M. Stewart

doi:10.1111/j.2042-7158.1980.tb10905.x

Cited by 15 publications

(6 citation statements)

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“…The calculated log P values for the compounds in this study all fell within the range 2.1-4.6, similar to the values investigated by Dearden et al (1980). However, unlike the previous study, no overall correlation was found between log P and in-vivo analgesic or antiinflammatory activity.…”

Section: Rationale For Compound Selectionsupporting

confidence: 82%

“…The log P values calculated for compounds 1, 2 and 3 were 2.1, 2.8 and 4.4, respectively, (MedChem software, version 3.52, Medicinal Chemistry Project, Pomona College, USA). These values all fall within the range in which the second parabolic relationship had been demonstrated by Dearden et al (1980). The compounds were therefore predicted to possess anti-inflammatory activity.…”

Section: Rationale For Compound Selectionsupporting

confidence: 64%

“…In this study a series of paracetamol derivatives was designed and tested for analgesic and anti-inflammatory activity. The work follows on from the findings of O'Hara (1976) and Dearden et al (1980) vide supra. One important consideration in the design of anti-inflammatory drugs is the problem of gastric irritancy, the most common side effect associated with NSAIDs.…”

Section: Rationale For Compound Selectionmentioning

confidence: 99%

“…Continuing this work, O'Hara (1976) showed that a parabolic relationship existed between analgesic activity and log P of ringsubstituted alkyl derivatives of paracetamol, where log P was less than 1.8. Dearden et al (1980) later extended this range of compounds to include derivatives in which the log P was increased to 4.4. In this extended series, a second parabolic relationship was apparent in the log P range 1.…”

Section: Introductionmentioning

confidence: 99%

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Design, synthesis and biological testing of a novel series of anti-inflammatory drugs

Duffy

Dearden

Rostron

2001

Journal of Pharmacy and Pharmacology

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Many of the non-steroidal anti-inflammatory drugs (NSAIDs) currently marketed produce severe gastro-toxic side effects. The benefits of producing NSAIDs without these side effects are obvious, particularly for patients requiring long-term therapy. The aim of this investigation was to produce novel NSAIDs, based on paracetamol, that exhibit little or no gastro-toxicity. The work covers design, synthesis and testing of 13 drug candidates. The analgesic and anti-inflammatory potencies of the drug candidates were measured using the mouse abdominal constriction assay and the carrageenan-induced rat paw oedema assay, respectively. The stomachs of the rats were examined post-mortem, to assess the gastro-toxicity of the drugs. Of the 13 compounds described herein, 11 were shown to possess analgesic activity at 2-10 times the potency of aspirin, while 8 demonstrated anti-inflammatory activity at 3-10 times the potency of aspirin. Significantly, all of the compounds showed very low gastro-toxicity when compared with aspirin. The results of this study indicate that it is possible to develop novel, potent NSAIDs based on the structure of paracetamol. These compounds have the advantage of demonstrating much lower gastro-toxicity than NSAIDs currently available. Drugs of this type may, in future, provide effective treatments for inflammatory disorders.

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Section: Rationale For Compound Selectionsupporting

confidence: 82%

Section: Rationale For Compound Selectionsupporting

confidence: 64%

Section: Rationale For Compound Selectionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Design, synthesis and biological testing of a novel series of anti-inflammatory drugs

Duffy

Dearden

Rostron

2001

Journal of Pharmacy and Pharmacology

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“…This theory is vulnerable to the same criticism as that of Franke's earlier theory regarding biphasic curves (47). We prefer, as a general theory, the concept of two different receptors having different lipophilic requirements and showed (64) that the Penniston model, modified by two receptor side-compartments, could account satisfactorily for such doublepeaked QSARs.…”

Section: Partitioning and Penetrationmentioning

confidence: 99%

Partitioning and Lipophilicity in Quantitative Structure-Activity Relationships

Dearden¹

1985

Environmental Health Perspectives

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The history of the relationship of biological activity to partition coefficient and related properties is briefly reviewed. The dominance of partition coefficient in quantitation of structure-activity relationships is emphasized, although the importance of other factors is also demonstrated.Various mathematical models of in vivo transport and binding are discussed; most of these involve partitioning as the primary mechanism of transport. The models describe observed quantitative structureactivity relationships (QSARs) well on the whole, confirming that partitioning is of key importance in in vivo behavior of a xenobiotic. The partition coefficient is shown to correlate with numerous other parameters representing bulk, such as molecular weight, volume and surface area, parachor and calculated indices such as molecular connectivity; this is especially so for apolar molecules, because for polar molecules lipophilicity factors into both bulk and polar or hydrogen bonding components. The relationship of partition coefficient to chromatographic parameters is discussed, and it is shown that such parameters, which are often readily obtainable experimentally, can successfully supplant partition coefficient in QSARs.The relationship of aqueous solubility with partition coefficient is examined in detail. Correlations are observed, even with solid compounds, and these can be used to predict solubility. The additive/constitutive nature of partition coefficient is discussed extensively, as are the available schemes for the calculation of partition coefficient.Finally the use of partition coefficient to provide structural information is considered. It is shown that partition coefficient can be a valuable structural tool, especially if the enthalpy and entropy of partitioning are available.

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Theoretical approaches to drug design and biological activity: II. Multivariate structure‐activity relationships in combination with the multivariate bioassay (MASCA Model)

Mager

1983

Medicinal Research Reviews

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A Double-Peaked Quantitive Structure-Activity Relationship (Qsar) in A Series of Paracetamol Derivatives

Cited by 15 publications

References 0 publications

Design, synthesis and biological testing of a novel series of anti-inflammatory drugs

Design, synthesis and biological testing of a novel series of anti-inflammatory drugs

Partitioning and Lipophilicity in Quantitative Structure-Activity Relationships

Theoretical approaches to drug design and biological activity: II. Multivariate structure‐activity relationships in combination with the multivariate bioassay (MASCA Model)

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