In vitro and in vivo pharmacological characterization of SB 201993, an eicosanoid-like LTB4 receptor antagonist with anti-inflammatory activity.
Leukotriene B4 (LTB4) and 12-(R)-hydroxy-5,8,10,14-eicosatetraenoic acid (12-[R]-HETE) have been postulated to contribute to the pathophysiology of inflammatory diseases. SB 201993, (E)-3-[[[[6-(2-carboxyethenyl)-5-[[8-(4-methoxyphenyl)octyl] oxy]-2-pyridinyl] methyl] thio] methyl] benzoic acid, identified from a chemical series designed as ring-fused analogs of LTB4, was evaluated as an antagonist of LTB4- and 12-(R)-HETE-induced responses in vitro and for anti-inflammatory activity in vivo. SB 201993 competitively antagonized [3-H]-LTB4 binding to intact human neutrophils (Ki = 7.6 nM) and to membranes of RBL 2H3 cells expressing the LTB4 receptor (RBL 2H3-LTB4R; IC50 = 154 nM). This compound demonstrated competitive antagonism of LTB4- and 12-(R)-HETE-induced Ca2+ mobilization responses in human neutrophils (IC50s of 131 nM and 105 nM, respectively) and inhibited LTB4-induced Ca2+ mobilization in human cultured keratinocytes (IC50 = 61 nM), RBL 2H3-LTB4R cells (IC50 = 255 nM) and mouse neutrophils (IC50 = 410 nM). SB 201993 showed weak LTD4-receptor binding affinity (Ki = 1.9 microM) and inhibited 5-lipoxygenase (IC50 of 3.6 microM), both in vitro and ex vivo. In vivo, SB 201993 inhibited LTB4-induced neutrophil infiltration in mouse skin and produced dose-related, long lasting topical anti-inflammatory activity against the fluid and cellular phases of arachidonic acid-induced mouse ear inflammation (ED50 of 580 microg/ear and 390 microg/ear, respectively). Similarly, anti-inflammatory activity was also observed in the murine phorbol ester-induced cutaneous inflammation model (ED50 of 770 and 730 microg/ear, respectively, against the fluid and cellular phases). These results indicate that SB 201993 blocks the actions of LTB4 and 12-(R)-HETE and inhibits a variety of inflammatory responses; and thus may be a useful compound to evaluate the role of these mediators in disease models.
Sarau
H M
HM
Department of Pulmonary Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939, USA. skip_sarau-1@SBPHRD.COM
Foley
J J
JJ
Schmidt
D B
DB
Martin
L D
LD
Webb
E F
EF
Tzimas
M N
MN
Breton
J J
JJ
Chabot-Fletcher
M
M
Underwood
D C
DC
Hay
D W
DW
Kingsbury
W D
WD
Chambers
P A
PA
Pendrak
I
I
Jakas
D R
DR
Sathe
G M
GM
Van Horn
S
S
Daines
R A
RA
Griswold
D E
DE
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D001667:Binding, Competitive; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000097:blood / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D006168:Guinea Pigs; D006801:Humans; D007476:Ionophores / Q000494:pharmacology; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D007975:Leukotriene B4 / Q000097:blood / Q000494:pharmacology; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors*
D000893:Anti-Inflammatory Agents; D001565:Benzoates; D007476:Ionophores; D011725:Pyridines; D018102:Receptors, Leukotriene B4; C083427:(E)-3-((((6-(2-carboxyethenyl)-5-((8-(4-methoxyphenyl)octyl)oxy)-2-pyridinyl)methyl)thio)methyl)benzoic acid; D007975:Leukotriene B4; D000001:Calcimycin; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D002118:Calcium