RESUMO
A series of omega-[(4-phenyl-2-quinolyl)oxy]alkanoic acid derivatives was prepared which inhibited the binding of the leukotriene B4 to its receptors on guinea pig spleen membranes and on human polymorphonuclear leukocytes. A structure-activity relationship was investigated. The length of the carboxylic acid side chain was important for potent binding activity. The replacement of the oxygen atom at the beginning of the chain with other polar or nonpolar linking groups led to considerable loss of potency, indicating that the oxygen linking atom might be involved in the receptor recognition. alpha-Substitution on the carboxylic acid side chain led to substantially more potent compounds. Substitution on the phenyl ring and on the quinoline ring was also evaluated.
Assuntos
Leucotrieno B4/antagonistas & inibidores , Quinolonas/síntese química , Animais , Cobaias , Humanos , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Quinolonas/farmacologia , Receptores Imunológicos/efeitos dos fármacos , Receptores Imunológicos/metabolismo , Receptores do Leucotrieno B4 , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Ácidos Carboxílicos/síntese química , Leucotrieno B4/antagonistas & inibidores , Piridinas/síntese química , Tetrazóis/síntese química , Administração Oral , Animais , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Cobaias , Humanos , Leucotrieno B4/metabolismo , Neutrófilos/efeitos dos fármacos , Piridinas/química , Piridinas/farmacologia , Coelhos , Receptores Imunológicos/metabolismo , Receptores do Leucotrieno B4 , Baço/efeitos dos fármacos , Baço/metabolismo , Relação Estrutura-Atividade , Tetrazóis/química , Tetrazóis/farmacologiaRESUMO
A series of omega-[(omega-arylalkyl)thienyl]alkanoic acid isomers was prepared and a structure-activity relationship was investigated. These compounds have displayed either LTA4 hydrolase inhibition activities or LTB4 receptor binding activities, or both, depending on the relative orientation of the two side chains on the thiophene ring. Whereas the 2,5-isomers specifically exhibited LTA4 hydrolase inhibition, 3,5-isomers displayed both activities. On the other hand, the "ortho-isomers" specifically inhibited the binding of the LTB4 to its receptor. The side-chain lengths were also important for an optimal inhibition or binding activity. Substitutions on the terminal aromatic ring or on the thiophene nucleus led to small changes in both activities. The most dramatic effect was obtained by substituting the carboxylic acid side chain in the alpha-position with one or two methyl groups, which substantially enhanced the LTB4 receptor binding activity. In the most favorable case, the alpha,alpha-dimethyl derivative RP66153 was found 20-fold more potent than its linear counterpart.