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Effects of the novel anti‐inflammatory compounds, N‐[2‐(cyclohexyloxy)‐4‐nitrophenyl] methanesulphonamide (NS‐398) and 5‐methanesulphonamido‐6‐(2, 4‐difluorothiophenyl)‐1‐indanone (L‐745, 337), on the cyclo‐oxygenase activity of human blood prostaglandin endoperoxide synthases
Author(s) -
Panara Maria R.,
Greco Anita,
Santini Giovanna,
Sciulli Maria G.,
Rotondo Maria T.,
Padovano Roberto,
Giamberardino Maria,
Cipollone Francesco,
Cuccurullo Franco,
Patrono Carlo,
Patrignani Paola
Publication year - 1995
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1995.tb15091.x
Subject(s) - chemistry , radioimmunoassay , platelet , monocyte , ketoprofen , thromboxane b2 , ic50 , prostaglandin , pharmacology , lipopolysaccharide , enantiomer , aspirin , medicine , endocrinology , in vitro , biochemistry , stereochemistry , chromatography
1 We have evaluated the selectivity of ketoprofen and two novel nonsteroidal anti‐inflammatory drugs, N‐[2‐(cyclohexyloxy)‐4‐nitrophenyl]methanesulphonamide (NS‐398) and 5‐methanesulphonamido‐6‐(2, 4‐difluorothiophenyl)‐1‐indanone (L‐745, 337), in inhibiting the cyclo‐oxygenase activity of prostaglandin endoperoxide synthase‐2 (PGHS‐2) vs PGHS‐1 in human blood monocytes and platelets, respectively. 2 Heparinized whole blood samples were drawn from healthy volunteers pretreated with aspirin, 300 mg 48 h before sampling, to suppress the activity of platelet PGHS‐1 and incubated at 37°C for 24 h with increasing concentrations of the test compounds in the presence of lipopolysaccharide (LPS, 10 μg ml −1 ). Immunoreactive PGE 2 levels were measured in plasma by a specific radioimmunoassay as an index of the cyclo‐oxygenase activity of LPS‐induced monocyte PGHS‐2. 3 The effects of the same inhibitors on platelet PGHS‐1 activity were assessed by allowing whole blood samples, drawn from the same subjects in aspirin‐free periods, to clot at 37°C for 1 h in the presence of the compounds and measuring immunoreactive thromboxane B 2 (TXB 2 ) levels in serum by a specific radioimmunoassay. 4 Under these experimental conditions, ketoprofen enantioselectively inhibited the cyclo‐oxygenase activity of both PGHS‐1 and PGHS‐2 with equal potency (IC 50 ratio: approx. 0.5 for both enantiomers), while L‐745, 337 and NS‐398 achieved selective inhibition of monocyte PGHS‐2 (IC 50 ratio: > 150). L‐745, 337 and NS‐398 did not affect LPS‐induced monocyte PGHS‐2 biosynthesis to any detectable extent. 5 We conclude that L‐745, 337 and NS‐398 are selective inhibitors of the cyclo‐oxygenase activity of human monocyte PGHS‐2. These compounds may provide adequate tools to test the contribution of this novel pathway of arachidonate metabolism to human inflammatory disease.