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Selected Publication:
Berg, J; Fellier, H; Christoph, T; Kremminger, P; Hartmann, M; Blaschke, H; Rovensky, F; Towart, R; Stimmeder, D.
Pharmacology of a selective cyclooxygenase-2 inhibitor, HN-56249: a novel compound exhibiting a marked preference for the human enzyme in intact cells.
Naunyn Schmiedebergs Arch Pharmacol. 2000; 361(4):363-372
Doi: 10.1007/s002109900192
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- Berg Jörg
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- Abstract:
- HN-56249 (3-(2,4-dichlorothiophenoxy)-4-methylsulfonylamino-benzenesu lfonamide), a highly selective cyclooxygenase (COX)-2 inhibitor, is the prototype of a novel series of COX inhibitors comprising bicyclic arylethersulfonamides; of this series HN-56249 is the most potent and selective human COX-2 inhibitor. HN-56249 inhibited platelet aggregation as a measure of COX-1 activity only moderately (IC50 26.5+/-1.7 microM). In LPS-stimulated monocytic cells the release of prostaglandin (PG) F1alpha as a measure of COX-2 was markedly inhibited (IC50 0.027+/-0.001 microM). Thus, HN-56249 showed an approximately 1000-fold selectivity for COX-2 in intact cells. In whole blood assays HN-56249 showed a potent inhibitory activity for COX-2 (IC50 0.78+/-0.37 microM) only. COX-1 was only weakly inhibited (IC50 867+/-181 microM). Hence, HN-56249 exhibited a greater than 1000-fold selectivity for whole blood COX-2. HN-56249 surpassed the COX-2 selectivities of the COX-2 selective inhibitors 3-cyclohexyloxy-4-methylsulfonylamino-nitrobenzene (NS-398) and 6-(2,4-difluorophenoxy)-5-methyl-sulfonylamino-1-indanone (flosulide) in the intact cell assays by eight- and threefold, respectively, and in the whole blood assays by approximately 40-fold. Following i.v. administration HN-56249 inhibited carrageenan-induced rat paw oedema only moderately (ID50 26.2+/-5.7 mg/kg, mean +/- SEM), approximately tenfold less potent than indomethacin (ID50 2.1+/-0.2 mg/kg, mean +/- SEM). After oral administration HN-56249 reversed thermal hyperalgesia in the carrageenan-induced rat paw oedema test, however, some 30-fold less potently than diclofenac. Comparing the inhibitory potency of HN-56249 against human COX-2 with that against murine COX-2 in intact cells revealed a 300-fold selectivity for the human enzyme. Similar effects were observed with other COX-2-selective arylethersulfonamides. In contrast, non-COX-2-selective arylethersulfonamides, including a highly selective COX-1 inhibitor, inhibited human and murine COX-2 approximately equipotently. In conclusion, HN-56249 is a novel potent and highly selective COX-2 inhibitor with a marked preference for the human COX-2 enzyme in vitro. Despite excellent bioavailability and the long plasma half-life of HN-56249, anti-inflammatory effects in rodents were only moderate. We suggest these differing in vitro-in vivo effects observed could be due to significant inflammatory prostaglandin synthesis by COX-1, or to the genetic differences between human and rodent COX-2, or to both.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Carrageenan -
- Cell Line -
- Cyclooxygenase 1 -
- Cyclooxygenase 2 -
- Cyclooxygenase 2 Inhibitors -
- Cyclooxygenase Inhibitors - chemistry Cyclooxygenase Inhibitors - pharmacology
- Edema - chemically induced Edema - pathology Edema - physiopathology
- Humans -
- Hyperalgesia - physiopathology
- Indans - chemistry Indans - pharmacology
- Isoenzymes - blood Isoenzymes - pharmacology
- Male -
- Membrane Proteins -
- Prostaglandin-Endoperoxide Synthases - blood Prostaglandin-Endoperoxide Synthases - pharmacology
- Rats -
- Rats, Sprague-Dawley -
- Reaction Time - drug effects
- Sulfonamides - chemistry Sulfonamides - pharmacology
- Find related publications in this database (Keywords)
- prostaglandin
- COX-1
- COX-2
- COX-2 inhibition
- non-steroidal anti-inflammatory drugs
- selective COX-2 inhibitor