(E)-3-[6-[[(2,6-dichlorophenyl)thio]methyl]-3-(2-phenylethoxy)-2- pyridinyl]-2-propenoic acid: a high-affinity leukotriene B4 receptor antagonist with oral antiinflammatory activity.
An extensive structure-activity study based around the high-affinity leukotriene B4 (LTB4) receptor antagonist SB 201146 (1) led to the identification of (E)-3-[6-[[(2,6-dichlorophenyl)-thio]methyl]-3-(2-phenylethoxy)-2- pyridinyl]-2-propenoic acid (3). This compound displays high affinity for the human neutrophil LTB4 receptor (Ki = 0.78 nM), blocks LTB4-induced Ca2+ mobilization with an IC50 of 6.6 +/- 1.5 nM, and demonstrates potent oral and topical antiinflammatory activity in a murine model of dermal inflammation.
Daines
R A
RA
Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939, USA.
Chambers
P A
PA
Foley
J J
JJ
Griswold
D E
DE
Kingsbury
W D
WD
Martin
L D
LD
Schmidt
D B
DB
Sham
K K
KK
Sarau
H M
HM
D000179:Acrylates / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents; D016718:Arachidonic Acid; D002118:Calcium / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007975:Leukotriene B4 / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D009504:Neutrophils / Q000378:metabolism / Q000648:ultrastructure; D010031:Otitis / Q000139:chemically induced / Q000188:drug therapy; D011725:Pyridines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000179:Acrylates; D000893:Anti-Inflammatory Agents; D011725:Pyridines; D018102:Receptors, Leukotriene B4; C084128:SB 201146; D007975:Leukotriene B4; D016718:Arachidonic Acid; C093304:Ticolubant; D002118:Calcium