Synthesis and biochemical/pharmacological profile of the novel leukotriene B4 receptor antagonist sodium (1S*, 3S*)-1-hydroxy-3-[(3 R*S*,E)-3-hydroxy-7-phenyl-1-hepten-1-yl]-1-cyclohexane acetate.
A novel series of leukotriene B4 (LTB4) antagonists is reported. These compounds present a cyclohexane ring in their chemical structure, which mimics the three conjugated double bonds of LTB4. The biochemical/pharmacological profile of the leader compound, PH-163 (sodium (1S*,3S*)-1-hydroxy-3-[(3R*S,E)-3-hydroxy-7-phenyl-1-hepten-1-yl]- 1 -cyclohexane acetate, CAS 163251-41-0) is described. This compound competes with [3H]LTB4 binding to its receptor in human neutrophils and guinea pig lung membranes with IC50's of 0.8 mumol/l and 0.2 mumol/l, respectively, i.e. relative binding affinities of 1% as compared to LTB4. PH-163 does not elicit any agonist activity, but inhibits leucocyte chemotaxis induced by LTB4 (pKB = 6.57) and lung parenchymal strip contraction (IC50 = 0.1 mumol/l). In conclusion, PH-163 or derivatives could be useful in the treatment of inflammatory diseases where LTB4 seems to be involved.
Hullot
P
P
Laboratoire de Chimie Biomoléculaire et des Interactions Biologiques, Centre National pour la Recherche Scientifique (U5074), Université Montpellier I, France.
Poudrel
J M
JM
Muller
A
A
Escale
R
R
Rossi
J C
JC
Girard
J P
JP
Bonne
C
C
D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003511:Cyclohexanols / Q000138:chemical synthesis* / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007975:Leukotriene B4 / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors*; D013055:Spectrophotometry, Infrared; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism
D003511:Cyclohexanols; D018102:Receptors, Leukotriene B4; C104857:PH 163; D007975:Leukotriene B4