Synthesis and Structure of Steroidal 4-Pregneno [3,2-c]Pyrazoles. A Novel Class of Potent Anti-Inflammatory Steroids

Hirschmann, Ralph; Steinberg, N. G.; Buchschacher, P.; Fried, J. H.; Kent, Gerald J.; Tishler, Max; Steelman, Sanford L.

doi:10.1021/ja00884a034

Cited by 59 publications

(13 citation statements)

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“…The superiority of p-fluorophenyl over phenyl, possibly for electronic as well as metabolic reasons, has been demonstrated in many medicinal chemical studies. Its effectiveness in anti-inflammatory agents such as pfluorophenyl(3,2-c)-pyrazole steroids(Figure 3f;Hirschmann et al, 1963;Strachan et al, 1964) and 4'-fluorobiphenyl-a-propionic acid(Figure 3g; was also observed in our previous in-vestigations. The synthesis of flufenisal was carried out in 1964…”

supporting

confidence: 78%

Discovery of diflunisal.

Hannah¹,

Ruyle²,

Jones³

et al. 1977

Brit J Clinical Pharma

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I Diflunisal (MK-647; 5-(2,4-difluorophenyl)-salicylic acid) is a new analgesic anti-inflammatory agent discovered after an extensive chemical and pharmacological study from 1962-71. 2 In the search for a superior salicylate our objectives were higher potency, better tolerance, and a longer duration of action. 3 An evaluation of many available and newly synthesized salicylates, in the granuloma and carrageenan foot oedema assays, revealed the activity-enhancing trend of a hydrophobic group-for example, phenyl, at the carbon-5 position of salicylic acid. 4 The attachment of a 5-(4-fluorophenyl) group, previously found to enhance the potency of antiinflammatory (3,2-c)-pyrazole steroids and phenyl-a-propionic acids to acetyl salicylic acid yielded a clinical candidate flufenisal. As an analgesic, flufenisal is two times more potent than aspirin in man, but with a longer action; no distinct advantage in gastrointestinal tolerance has, however, been observed. 5 Further investigation of 5-heteroaryl salicylic acids, flufenisal congeners and their non-acylating carbonate esters identified diflunisal and 5-( l-pyrryl)-salicylic acid for subacute safety assessment. The O-acetyl group, commonly present in aspirin, benorylate and flufenisal, was purposely avoided in these two compounds for safety considerations. 6 Without an O-acetyl group, diflunisal cannot acetylate proteins and macro-molecules in vivo as aspirin does. In the prostaglandin synthetase assay in vitro, salicylic acid is much less active than aspirin. In contrast, the non-acetylated diflunisal and desacetyl flufenisal are both more active than flufenisal in vitro. A significant difference between aspirin and diflunisal in their biochemical mechanisms was noted. 7 On the basis of overall efficacy and tolerance data, diflunisal was finally chosen as a superior analgesic anti-inflammatory salicylate for clinical evaluation.

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supporting

confidence: 78%

Discovery of diflunisal.

Hannah¹,

Ruyle²,

Jones³

et al. 1977

Brit J Clinical Pharma

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“…It has been shown in recent studies that incorporation of heteroatoms (N/O/S) enhances the biological activities of steroid molecules [1][2][3][4][5]. It was proved by various in vivo and in vitro assays which show significant antimicrobial, anti-inflammatory, hypotensive, hypocholesterolemic and diuretic activities [6][7][8][9][10][11][12][13][14][15]. Similarly, such effects have been shown by the most commonly used systemic glucocorticoids such as hydrocortisone, prednisolone and triamcinolone.…”

Section: Introductionmentioning

confidence: 96%

Discovery of a novel oxadiazine derivative of glucocorticoids endowed with DNA binding activities and molecular docking studies

Sultanat

Ali

Asif

et al. 2019

Journal of Taibah University for Science

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A series of new glucocorticoid oxadiazines (4-6) were synthesized by reacting glucocorticoids (1-3) with thiosemicarbazide and its derivatives. The structural assignment of products is confirmed on the basis of IR, 1 H NMR, 13 C NMR, MS and analytical data. The synthesized compounds (4-6) obeyed the Lipinski's "Rule of Five" analysis based on a computational prediction of molecular and pharmacokinetic properties. The interaction studies of compounds (4-6) with DNA were carried out by employing single-cell gel electrophoresis (comet assay), UV-vis and fluorescence spectroscopy. Compounds (4-6) were found capable of cellular DNA degradation breakage in isolated normal human lymphocytes. Viscometric and steady-state measurements further correlated with the comet assay studies. Hence, it could be suggested that the glucocorticoid compounds bearing a core oxadiazine scaffold would be a potent biological agent. Molecular docking studies further characterize the interaction of the synthesized compounds with DNA.

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“…There has been considerable interest in the synthesis and biological study of several heterocyclic steroids as extremely potent anti-in¯ammatory agents (Gupta et al, 1996, and references therein). It is known that 2 H -phenyl-11,17,21trihydroxy-16-methyl-20-oxo-4-pregneno[3,2-c]pyrazol-21-yl acetate and its p-¯urophenyl analogue are, respectively, 60 and 100 times more active than hydrocortisone (Hirschmann et al, 1963(Hirschmann et al, , 1964, and the importance of the [3,2-c]pyrazole function has been demonstrated by a number of investigators Hirschmann et al, 1963;Hannah et al, 1975). Both cortivazol and nivazol have the [3,2-c]pyrazole structural component, and the 3-keto function is absent, while both have been described as potent anti-in¯ammatory steroids (Gupta et al, 1996, and references therein).…”

Section: Commentmentioning

confidence: 99%

Two azasteroidal [3,2-c]pyrazole derivatives: 2′-(p-fluorophenyl)-4-azapyrazolo[4′,3′:2,3]-5α-androstan-17β-yl acetate and 2′-(p-fluorophenyl)-4-azapyrazolo[4′,3′:2,3]-5α-androstan-17β-ol

et al. 2003

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In both the title aza-steroids, 2'-(p-fluorophenyl)-4-azapyrazolo[4',3':2,3]-5alpha-androstan-17beta-yl acetate, C(27)H(34)FN(3)O(2), (I), and 2'-(p-fluorophenyl)-4-azapyrazolo[4',3':2,3]-5alpha-androstan-17beta-ol, C(25)H(32)FN(3)O, (II), the tetrahydropyridine ring adopts a half-chair conformation and is considerably strained as a consequence of the presence of the fused planar pyrazole ring. In both compounds, both cyclohexane rings have chair conformations, while the cyclopentane ring has an envelope conformation. All the rings of the steroid nucleus are trans fused. In (I), intermolecular N-H.O, C-H.F, C-H.O and C-H.N interactions are observed in the solid state, while intermolecular N-H.O and O-H.N hydrogen bonds are observed in (II).

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Synthesis and Structure of Steroidal 4-Pregneno [3,2-c]Pyrazoles. A Novel Class of Potent Anti-Inflammatory Steroids

Cited by 59 publications

References 0 publications

Discovery of diflunisal.

Discovery of diflunisal.

Discovery of a novel oxadiazine derivative of glucocorticoids endowed with DNA binding activities and molecular docking studies

Two azasteroidal [3,2-c]pyrazole derivatives: 2′-(p-fluorophenyl)-4-azapyrazolo[4′,3′:2,3]-5α-androstan-17β-yl acetate and 2′-(p-fluorophenyl)-4-azapyrazolo[4′,3′:2,3]-5α-androstan-17β-ol

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