omega-[(4,6-Diphenyl-2-pyridyl)oxy]alkanoic acid derivatives: a new family of potent and orally active LTB4 antagonists.
A series of omega-[(4,6-diphenyl-2-pyridyl)oxy]alkanoic acid derivatives was prepared which inhibited the binding of leukotriene B4 to its receptors on guinea pig spleen membranes and on human polymorphonuclear leukocytes (PMNs) and selectively antagonized the LTB4-induced elastase release in human PMNs. On the basis of these three screens, a structure-activity relationship was investigated. alpha-Substitution on the carboxylic acid side chain led to only small changes in the binding affinities but greatly enhanced the LTB4 antagonist activity. Substitution on the phenyl rings was also evaluated. The terminal carboxylic acid function can be replaced by a tetrazole ring without loss in activity. The best in vitro LTB4 antagonists of this series were investigated in vivo in the inhibition of LTB4-induced leukopenia in rabbits. Compound 9b (RP69698) displayed potent LTB4 antagonist activity, after oral administration, with an ED50 value of 6.7 mg/kg.
Labaudinière
R
R
Rhône-Poulenc Rorer, Centre de Recherche de Vitry-Alfortville, Departement de Chimie Pharmaceutique et de Biologie, Vitry sur Seine, France.
Dereu
N
N
Cavy
F
F
Guillet
M C
MC
Marquis
O
O
Terlain
B
B
D000284:Administration, Oral; D000818:Animals; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D011971:Receptors, Immunologic / Q000378:metabolism; D018102:Receptors, Leukotriene B4; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D002264:Carboxylic Acids; D011725:Pyridines; D011971:Receptors, Immunologic; D018102:Receptors, Leukotriene B4; D013777:Tetrazoles; D007975:Leukotriene B4