The in vitro and in vivo pharmacologic activity of the potent and selective leukotriene B4 receptor antagonist CP-105696.
CP-105696, (+)-1-(3S,4R)-[3-(4-phenyl-benzyl)-4-hydroxy-chroman-7-yl] cyclopentane carboxylic acid, is a structurally novel, selective and potent leukotriene B4 (LTB4) receptor antagonist. In vitro, CP-105696 inhibited [3H]LTB4 (0.3 nM) binding to high-affinity LTB4 receptors on human neutrophils with an IC50 value of 8.42 +/- 0.26 nM. Scatchard analyses of [3H]LTB4 binding to these high-affinity receptors indicated that CP-105696 acted as a noncompetitive antagonist. CP-105696 inhibited human neutrophil chemotaxis mediated by LTB4 (5 nM) in a noncompetitive manner with an IC50 value of 5.0 +/- 2.0 nM. Scatchard analyses of [3H]LTB4 binding to low-affinity receptors on neutrophils indicated that CP-105696 acted as a competitive antagonist at this receptor, and inhibition of LTB4-mediated CD11b upregulation on human neutrophils was competitively inhibited by CP-105696 (pA2 = 8.03 +/- 0.19). CP-105696 at 10 microM did not inhibit either human neutrophil chemotaxis or CD11b upregulation mediated through alternate (i.e., C5a, IL-8, PAF) G-protein coupled chemotactic factor receptors. In isolated human monocytes, LTB4 (5 nM)-mediated Ca++ mobilization was inhibited by CP-105696 with an IC50 value of 940 +/- 70 nM. In vivo, after oral administration, CP-105696 blocked neutrophil and eosinophil infiltration in cavine dermis mediated by either LTB4 or arachidonic acid with ED50 values of 0.3 +/- 0.1 mg/kg. 12(R)-Hydroxyeicosatetraenoic acid-mediated neutrophil infiltration was blocked by 76.4 +/- 14.8% at 3 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)
Showell
H J
HJ
Department of Immunology and Infectious Diseases, Pfizer Inc, Groton, Connecticut, USA.
Pettipher
E R
ER
Cheng
J B
JB
Breslow
R
R
Conklyn
M J
MJ
Farrell
C A
CA
Hingorani
G P
GP
Salter
E D
ED
Hackman
B C
BC
Wimberly
D J
DJ
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002264:Carboxylic Acids / Q000494:pharmacology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004804:Eosinophils / Q000187:drug effects / Q000502:physiology; D006168:Guinea Pigs; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D020024:Leukotriene Antagonists; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors*; D016177:Macrophage-1 Antigen / Q000032:analysis; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000502:physiology; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology
D001578:Benzopyrans; D002264:Carboxylic Acids; D006893:Hydroxyeicosatetraenoic Acids; D020024:Leukotriene Antagonists; D016177:Macrophage-1 Antigen; D007975:Leukotriene B4; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D002118:Calcium; C089698:CP 105696