Preclinical pharmacology profile of CS-706, a novel cyclooxygenase-2 selective inhibitor, with potent antinociceptive and anti-inflammatory effects

Ushiyama, Shigeru; Yamada, Tomoko; Murakami, Yūichiro; Kumakura, Seiichiro; Inoue, Shinichi; Suzuki, Keisuke; Nakao, Akira; Kawara, Akihiro; Kimura, Tomio

doi:10.1016/j.ejphar.2007.08.034

Cited by 36 publications

(28 citation statements)

References 31 publications

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“…This pharmacokinetic feature (i.e., high volume of distribution) might translate into fast clearance from side effect compartments (including vascular wall, heart, and kidney). 31 This possibility will be explored in further studies.…”

Section: Discussionmentioning

confidence: 98%

“…The discrepancy between these results and those found in the cell-based assay could be due to a different inhibitor sensitivity exhibited by the mouse and human COX isozymes, as already reported for other anti-inflammatory compounds. 10 As a matter of the fact, such a dramatic loss in COX inhibitory potency and a drop in selectivity under the HWB assay conditions are common to other selective COX-2 inhibitors, such as valdecoxib, 31,32 etoricoxib, 31,32 lumiracoxib, 33 and rofecoxib, 34,35 as well as tNSAIDs such as nimesulide 16,31 and meloxicam. 36,37 It should be pointed out that, according to the test, 10a, 10c, and 11c exhibited an affinity for COX-2 5-10-fold higher than that for COX-1, which should translate clinically into an acceptable GI safety, and allowing for a sufficient prostacyclin generation that should mitigate the CV effects showed by overly selective COX-2 inhibitors, as previously discussed.…”

Section: Resultsmentioning

confidence: 99%

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Novel Ester and Acid Derivatives of the 1,5-Diarylpyrrole Scaffold as Anti-Inflammatory and Analgesic Agents. Synthesis and in Vitro and in Vivo Biological Evaluation

et al. 2009

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A new generation of selective cyclooxygenase-2 (COX-2) inhibitors (coxibs) was developed to circumvent the major side effects of cyclooxygenase-1 (COX-1) and COX-2 inhibitors (stomach ulceration and nephrotoxicity). As a consequence, coxibs are extremely valuable in treating acute and chronic inflammatory conditions. However, the use of coxibs, such as rofecoxib (Vioxx), was discontinued because of the high risk of cardiovascular adverse events. More recent clinical findings highlighted how the cardiovascular toxicity of coxibs could be mitigated by an appropriate COX-1 versus COX-2 selectivity. We previously reported a set of substituted 1,5-diarylpyrrole derivatives, selective for COX-2. Here, we describe the synthesis of new 1,5-diarylpyrroles along with their inhibitory effects in vitro, ex vivo, and in vivo toward COX isoenzymes and their analgesic activity. Isopropyl-2-methyl-5-[4-(methylsulfonyl)phenyl]-1-phenyl-1H-pyrrole-3-acetate (10a), a representative member of the series, was selected for pharmacokinetic and metabolic studies.

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Section: Discussionmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Novel Ester and Acid Derivatives of the 1,5-Diarylpyrrole Scaffold as Anti-Inflammatory and Analgesic Agents. Synthesis and in Vitro and in Vivo Biological Evaluation

et al. 2009

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“…Thus, a dramatic loss in COX inhibition potency and drop in selectivity when using the human whole blood assays are shared with other selective COX-2 inhibitors such as valdecoxib [33,34], etoricoxib [33,34], lumiracoxib [35] and rofecoxib [36,37] as well as (t)NSAID such as nimesulide [33,38] and meloxicam [39,40].…”

Section: Biological and Pharmacological Evaluationmentioning

confidence: 99%

Enlarging the NSAIDs Family: Ether, Ester and Acid Derivatives of the 1,5-Diarylpyrrole Scaffold as Novel Anti-Inflammatory and Analgesic Agents

Biava

Porretta²,

Poce³

et al. 2011

CMC

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Abstract:The development of the coxib family has represented a stimulating approach in the treatment of inflammatory disorders, such as arthritis, and for the management of acute pains, in relation to the well-known traditional Non-Steroidal Anti-inflammatory Drugs (tNSAIDs). Prompted by the pursuit for new cyclooxygenase-2 (COX-2) inhibitors, endowed with fine tuned selectivity and high potency, in the past years we have identified novel classes of ether, ester and acid molecules characterized by the 1,5-diarylpyrrole scaffold as potentially powerful anti-inflammatory molecules (12-66). All compounds proved to exert an in vitro inhibition profile as good as that shown by reference compounds. Compounds bearing a p-methylsulfonylphenyl substituent at C5 displayed the best issues. In particular, ester derivatives proved to perform the best in vitro profile in terms of selectivity and activity toward COX-2. The cell-based assay data showed that an increase of hindrance at the C3 side chain of compounds could translate to activity enhancement. The human whole blood (HWB) test let to highlight that submitted compounds displayed 5-10 fold higher selectivity for COX-2 vs COX-1 which should translate clinically to an acceptable gastrointestinal safety and mitigate the cardiovascular effects highlighted by highly selective COX-2 inhibitors. Finally, to assess in vivo anti-inflammatory and analgesic activity three different tests (rat paw pressure, rat paw oedema and abdominal constriction) were performed. Results showed good in vivo anti-inflammatory and analgesic activities. The issues gained with these classes of compounds represent, nowadays, a potent stimulus for a further enlargement of the NSAIDs family. In this review we describe the results obtained by our research group on this topic.

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“…[76][77][78] it has a very short half-live in blood, its oxidization to 15-ketoprostaglandins is catalyzed by 15-hydroxyprostaglandin dehydrogenase In order to design any structure with pyrrole moiety or its fused form indole, vital considerations must be taken to ensure its anti-inflammatory activity. 32,74,79,80 First, the structure should consist of an acidic moiety (carboxylic acid, enols, ester etc.) attached to a planar, aromatic functional group (appears to correlate with the double bond of AA), 31 4-benzodioxine or pyrrole nucleus are described.…”

Section: Structure-activity Relationships (Sar)mentioning

confidence: 99%

“…Several derivatives, including (S indomethacin (Indacin ® ), acemetacin (Emflex ® ) and etodolac (Etodine ® ) as indole derivatives, and ketorolac (Ketolac ® ) as a pyrrole derivative. [33][34][35][36] These compounds blocked prostaglandin synthesis by non-selective inhibition of COX-1 and COX-2 (indomethacin, acemetacin, tolmetin and ketorolac) or by selective inhibition of COX-2 (etodolac) (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Structure Activity Relationship of Some Indole Derivatives as Potential Anti-inflammatory Agents

Fatahala

Khedr

Mohamed

2017

ACSi

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A series of fused pyrroles were synthesized and tested for their in vivo anti-inflammatory activity. Among 14 examined derivatives, 5 derivatives (1b-e, g and 5b), showed a promising anti-inflammatory activity equivalent to reference anti-inflammatory drugs (indomethacin and ibuprofen). A molecular docking study was conducted to interpret the biological activities of the tested compounds. The docking results were complementary with the phase of the biological survey and confirmed the biological effects.

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Preclinical pharmacology profile of CS-706, a novel cyclooxygenase-2 selective inhibitor, with potent antinociceptive and anti-inflammatory effects

Cited by 36 publications

References 31 publications

Novel Ester and Acid Derivatives of the 1,5-Diarylpyrrole Scaffold as Anti-Inflammatory and Analgesic Agents. Synthesis and in Vitro and in Vivo Biological Evaluation

Novel Ester and Acid Derivatives of the 1,5-Diarylpyrrole Scaffold as Anti-Inflammatory and Analgesic Agents. Synthesis and in Vitro and in Vivo Biological Evaluation

Enlarging the NSAIDs Family: Ether, Ester and Acid Derivatives of the 1,5-Diarylpyrrole Scaffold as Novel Anti-Inflammatory and Analgesic Agents

Synthesis and Structure Activity Relationship of Some Indole Derivatives as Potential Anti-inflammatory Agents

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