Pharmacology of a selective cyclooxygenase-2 inhibitor, HN-56249: a novel compound exhibiting a marked preference for the human enzyme in intact cells.
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.
Berg
J
J
Department of Pharmacology, Nycomed Austria, Linz. Joerg/Berg@akh.linz.at
Fellier
H
H
Christoph
T
T
Kremminger
P
P
Hartmann
M
M
Blaschke
H
H
Rovensky
F
F
Towart
R
R
Stimmeder
D
D
D000818:Animals; D002351:Carrageenan; D002460:Cell Line; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004487:Edema / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D006930:Hyperalgesia / Q000503:physiopathology; D007189:Indans / Q000737:chemistry / Q000494:pharmacology*; D007527:Isoenzymes / Q000097:blood / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000097:blood / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007189:Indans; D007527:Isoenzymes; D008565:Membrane Proteins; D013449:Sulfonamides; D002351:Carrageenan; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; C059178:flosulide