4,5-Diaryloxazole inhibitors of cyclooxygenase-2 (COX-2)

Talley, John J.; Bertenshaw, Stephen R.; Brown, David; Carter, Jeffery S.; Graneto, Mathew J.; Koboldt, Carol M.; Masferrer, Jaime L.; Norman, Bryan H.; Rogier, D. Joseph; Zweifel, Ben S.; Seibert, Karen

doi:10.1002/(sici)1098-1128(199905)19:3<199::aid-med1>3.0.co;2-7

Cited by 41 publications

(30 citation statements)

References 23 publications

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“…Although the selectivity is similar to that of the methyl ester of indomethacin, the potency is significantly enhanced by introduction of the nido ‐dicarbaborate. Its COX‐2 inhibitory activity in the nanomolar range is similar to that of SC‐299, a well‐characterized COXIB based on a diaryl oxazole (Figure , Table ) . To the best of our knowledge, this is the first nido ‐dicarbaborate‐containing inhibitor that shows such a significantly increased potency relative to its phenyl analogue.…”

Section: Figurementioning

confidence: 55%

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nido‐Dicarbaborate Induces Potent and Selective Inhibition of Cyclooxygenase‐2

Neumann

Sárosi

et al. 2015

ChemMedChem

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Carbaboranes are increasingly studied as pharmacophores, particularly as replacements for aromatic systems. However, especially ortho-carbaborane is prone to degradation of the cluster, which hampers biological application. This study demonstrates that deboronation of the cluster may not only lead to a more active analogue but can also improve the solubility and stability of a carbaborane-containing inhibitor. Notably, introduction of a nido-dicarbaborate cluster into the cyclooxygenase (COX) inhibitor indomethacin results in a remarkably increased inhibitory potency and selectivity for COX-2 relative to the respective phenyl analogue. The first crystal structure of a carbaborane-containing inhibitor bound to COX-2 further reveals a novel binding mode for the inhibitor that is strikingly different from that of indomethacin. These results indicate that nido-dicarbaborate is a promising pharmacophore exhibiting properties which are also highly beneficial for its introduction into other inhibitor classes.

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Section: Figurementioning

confidence: 55%

“…Its COX-2 inhibitory activity in the nanomolar range is comparable to that of SC-299, a well-characterized COXIB based on a diaryl oxazole (Scheme 1, Table 1). [13] To the best of our knowledge, this is the first nido -dicarbaborate-containing inhibitor which shows such a significantly increased potency relative to its phenyl analogue.…”

mentioning

confidence: 99%

nido‐Dicarbaborate Induces Potent and Selective Inhibition of Cyclooxygenase‐2

Neumann

Sárosi

et al. 2015

ChemMedChem

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“…[31,32] Pleasingly, the COX 1/2 data obtained was consistent with inhibitory potencies reported in literature. [33,34] 2.4 Antiproliferative activity and testosterone suppression.…”

Section: Akr1cs Selectivity and Cox Inhibitionmentioning

confidence: 99%

Hydroxytriazole derivatives as potent and selective aldo-keto reductase 1C3 (AKR1C3) inhibitors discovered by bioisosteric scaffold hopping approach

Pippione

Giraudo

Bonanni

et al. 2017

European Journal of Medicinal Chemistry

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The aldo-keto reductase 1C3 isoform (AKR1C3) plays a vital role in the biosynthesis of androgens, making this enzyme an attractive target for castration-resistant prostate cancer therapy. Although AKR1C3 is a promising drug target, no AKR1C3-targeted agent has to date been approved for clinical use. Flufenamic acid, a non-steroidal anti-inflammatory drug, is known to potently inhibit AKR1C3 in a non-selective manner as COX off-target effects are also observed. To diminish off-target effects, we have applied a scaffold hopping strategy replacing the benzoic acid moiety of flufenamic acid with an acidic hydroxyazolecarbonylic scaffold. In particular, differently N-substituted hydroxylated triazoles were designed to simultaneously interact with both subpockets 1 and 2 in the active site of AKR1C3, larger for AKR1C3 than other AKR1Cs isoforms. Through computational design and iterative rounds of synthesis and biological evaluation, novel compounds are reported, sharing high selectivity (up to 230-fold) for AKR1C3 over 1C2 isoform and minimal COX1 and COX2 off-target inhibition. A docking study of compound 8, the most interesting compound of the series, suggested that its methoxybenzyl substitution has the ability to fit inside subpocket 2, being involved in π-π staking interaction with Trp227 (partial overlapping) and in a T-shape π-π staking with Trp86. This compound was also shown to diminish testosterone production in the AKR1C3-expressing 22RV1 prostate cancer cell line while synergistic effect was observed when 8 was administered in combination with abiraterone or enzalutamide.

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“…First, to characterize the expression of COX-] and COX-2 mRNA in calluses at timed intervals after fracture. The second objective of this study was to compare the effects of daily administration of an analgesic dose of a nonselective NSAID ketorolac and parecoxib a COX-2 selective inhibitor on fracture repair [30]. Parecoxib is a pro-drug of valdecoxib, the second generation COX-2 selective inhibitor, which is approximately 1 00-fold more selective for COX-2 enzyme than celecoxib.…”

Section: Introductionmentioning

confidence: 99%

Differential inhibition of fracture healing by non‐selective and cyclooxygenase‐2 selective non‐steroidal anti‐inflammatory drugs

Gerstenfeld

Thiede²,

Seibert³

et al. 2003

Journal Orthopaedic Research

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320

217

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Non-steroidal anti-inflammatory drugs (NSAIDs) specifically inhibit cyclooxygenase (COX) activity and are widely used as antiarthritics, post-surgical analgesics, and for the relief of acute musculoskeletal pain. Recent studies suggest that non-specific KSAlDs, which inhibit both COX-I and COX-2 isoforms, delay bone healing. The objectives of this study were 2-fold; first, to measure the relative changes in the normal expression of COX-1 and COX-2 mRNAs over a 42 day period of fracture healing and second, to compare the effects of a commonly used non-specific NSAID, ketorolac, with a COX-2 specific NSAID, Parecoxib (a pro-drug of valdecoxib), on this process. Simple, closed, transverse fractures were generated in femora of male Sprague-Dawley rats weighing approximately 450 g each. Total RNA was prepared from the calluses obtained prior to fracture and at I , 3, 5, 7, 10, 14, 21, 35 and 42 days post-fracture and levels of COX-I and COX-2 mRNA were measured using real time PCR. While the relative levels of COX-1 inRNA remained constant over a 21-day period, COX-2 inRNA levels showed peak expression during the first 14 days of healing and returned to basal levels by day 21. Mechanical properties of the calluses were then assessed at 21 and 35 days postfracture in untreated animals and animals treated with either ketorolac or high or low dose parecoxib. At both 21 and 35 days after fracture, calluses in the group treated with the ketorolac showed a significant reduction in mechanical strength and stiffness when compared with controls (17 < 0.05). At the 21-day time point, calluses of the parecoxib treated animals showed a lower mean mechanical strength than controls, but the inhibition was not statistically significant. Based on physical analysis of the bones, 3 of 12 (25'%1) of the ketorolac-treated and 1 of 12 (8%) of the high dose parecoxib-treated animals showed failure to unite their fractures by 21 days, while all fractures in both groups showed union by 35 days. Histological analysis at 21 days showed that the calluses in the ketorolac-treated group contained substantial amounts of residual cartilage while neither the control nor the parecoxib-treated animals showed comparable amounts of cartilage at this stage. These results demonstrate that ketorolac and parecoxib delay fracture healing in this model, but in this study daily administration of ketorolac, a non-selective COX inhibitor had a greater affect on this process. They further demonstrate that a COX-2 selective NSAID, such as parecoxib (valdecoxib), has only a small effect on delaying fracture healing even at doses that are known to fully inhibit prostaglandin production.

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4,5-Diaryloxazole inhibitors of cyclooxygenase-2 (COX-2)

Cited by 41 publications

References 23 publications

nido‐Dicarbaborate Induces Potent and Selective Inhibition of Cyclooxygenase‐2

nido‐Dicarbaborate Induces Potent and Selective Inhibition of Cyclooxygenase‐2

Hydroxytriazole derivatives as potent and selective aldo-keto reductase 1C3 (AKR1C3) inhibitors discovered by bioisosteric scaffold hopping approach

Differential inhibition of fracture healing by non‐selective and cyclooxygenase‐2 selective non‐steroidal anti‐inflammatory drugs

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