Pharmacological profile of FK881(ASP6537), a novel potent and selective cyclooxygenase-1 inhibitor

Imanishi, Junko; Morita, Yoshiaki; Yoshimi, Eiji; Kuroda, Kanae; Masunaga, Taro; Yamagami, Kaoru; Kuno, Miyuki; Hamachi, Emi; Aoki, Satoshi; Takahashi, Fumie; Nakamura, Katsuya; Miyata, Susumu; Ohkubo, Y.; Mutoh, Seitaro

doi:10.1016/j.bcp.2011.06.035

Cited by 19 publications

(21 citation statements)

References 44 publications

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“…Despite the anti-inflammatory and analgesic benefits of COX-1 and COX-2 inhibition, this pathway is known to produce cytotoxic effects contributing to increased intestinal permeability and the formation of gastric ulcers (12,14,23). Furthermore, neither inhibition of COX-1 nor COX-2 alone was found to induce significant GI damage, rather, the combination of COX-1 and COX-2 inhibition along with an additional mechanism was hypothesized to contribute substantially to NSAID-induced intestinal injury (29,52).…”

mentioning

confidence: 99%

Effect of NSAIDs on Na⁺/H⁺ exchanger activity in rat colonic crypts

Roginiel

Kohut

Kaur

et al. 2013

American Journal of Physiology-Cell Physiology

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Nonsteroidal anti-inflammatory drugs (NSAIDs; 1) are widely recommended for several acute and chronic conditions. For example, both indomethacin and aspirin are taken for pain relief. Aspirin is also used for prevention of myocardial infarction, and indomethacin can be administered orally or as a suppository for patients with rheumatoid disease and other chronic inflammatory states. However, use of NSAIDs can cause damage to the mucosal barrier surrounding the gastrointestinal (GI) tract, increasing the risk of ulcer formation. While microencapsulation of NSAIDs has been shown to reduce upper GI injury, sustained release in the lower GI tract and colon may cause epithelial erosion due to increased acidification. The use of suppositories has also been linked to rectal and lower GI bleeding. In this study, we investigated the role of NSAIDs aspirin and indomethacin on Na+/H+ exchanger (NHE) activity in rat colonic crypts. By comparing average rates of pH recovery between control and NSAID perfusion runs, we were able to determine that both aspirin and indomethacin increase hydrogen extrusion into the colonic lumen. Through treatment with 5-ethylisopropyl amiloride (EIPA), amiloride, and zoniporide dihydrochloride, we further demonstrated that indomethacin specifically enhances proton excretion through regulation of apical NHE-3 and NHE-2 and to a lesser extent on basolateral NHE-1 and NHE-4. Our results suggest that clinical exposure to NSAIDs may affect colonic tissue at the site of selected NHE isoforms, resulting in modulation of transport and barrier function.

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confidence: 99%

Effect of NSAIDs on Na⁺/H⁺ exchanger activity in rat colonic crypts

Roginiel

Kohut

Kaur

et al. 2013

American Journal of Physiology-Cell Physiology

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“…1,2,4‐ and 1,2,3‐triazoles and their COXs inhibitory activities [ FK881 IC 50 values are by human whole blood assay (HWBA) . 10 – 12 IC 50 values are by a colorimetric assay (Cayman kit)].…”

Section: New Noteworthy Cox‐1 Selective Inhibitors (2010–2015)mentioning

confidence: 90%

“…However, unlike traditional NSAIDs, FK881 was better tolerated at GI tract, although its antipyretic effect was weak. Analgesic activity of FK881 resulted to be correspondent to that of classical NSAIDs in preclinical animal model, and may be useful in treating symptoms of rheumatoid arthritis and osteoarthritis, having a substantially improved GI side‐effect profile …”

Section: New Noteworthy Cox‐1 Selective Inhibitors (2010–2015)mentioning

confidence: 99%

COX‐1 Inhibitors: Beyond Structure Toward Therapy

Vitale

Panella

Scilimati

et al. 2016

Medicinal Research Reviews

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Biosynthesis of prostaglandins from arachidonic acid (AA) is catalyzed by cyclooxygenase (COX), which exists as COX-1 and COX-2. AA is in turn released from the cell membrane upon neopathological stimuli. COX inhibitors interfere in this catalytic and disease onset process. The recent prominent discovery involvements of COX-1 are mainly in cancer and inflammation. Five classes of COX-1 inhibitors are known up to now and this classification is based on chemical features of both synthetic compounds and substances from natural sources. Physicochemical interactions identification between such molecules and COX-1 active site was achieved through X-ray, mutagenesis experiments, specific assays and docking investigations, as well as through a pharmacometric predictive model building. All these insights allowed the design of new highly selective COX-1 inhibitors to be tested into those disease models in which COX-1 is involved. Particularly, COX-1 is expressed at high levels in the early to advanced stages of human epithelial ovarian cancer, and it also seems to play a pivotal role in cancer progression. The refinement of COX-1 selective inhibitor structure has progressed to the stage that some of the inhibitors described in this review could be considered as promising active principle ingredients of drugs and hence part of specific therapeutic protocols. This review aims to outline achievements, in the last 5 years, dealing with the identification of highly selective synthetic and from plant extracts COX-1 inhibitors and their theranostic use in neuroinflammation and ovarian cancer. Their gastrotoxic effect is also discussed.

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“…4-(5-Methyl-4-phenyl-1H-1,2,3-triazol-1-yl)benzenamine (18) [45]. The product was isolated as a brown solid (58% yield) by column chromatography (silica gel, petroleum ether/EtOAc ¼ 8:2); mp: 181e184 C. 1 (16) in dry CH 2 Cl 2 (5 mL). The reaction mixture was stirred and slowly allowed to reach room temperature.…”

Section: -Methyl-1-(4-nitrophenyl)-4-phenyl-1h-123-triazole (9)mentioning

confidence: 99%

“…1) is one of the most studied selective COX-1 inhibitors having the 1,2,4-triazole as a central ring [16]. In view of the various pharmacological properties of the triazole nucleus [17], herein we describe a new series of 1,4-diarylheterocycles bearing the 1,2,3-triazole (regioisomer of 1,2,4-triazole, chemical portion of FK881), as a core ring.…”

Section: Introductionmentioning

confidence: 99%