RESUMO
Various 1,2-isothiazolidine-1,1-dioxide (gamma-sultam) derivatives containing an antioxidant moiety, 2,6-di-tert-butylphenol substituent, were prepared. Some compounds, which have a lower alkyl group at the 2-position of the gamma-sultam skeleton, showed potent inhibitory effects on both cyclooxygenase (COX)-2 and 5-lipoxygenase (5-LO), as well as production of interleukin (IL)-1 in in vitro assays. They also proved to be effective in several animal arthritic models without any ulcerogenic activities. Among these compounds, (E)-(5)-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-ethyl-1, 2-isothiazolidine-1,1-dioxide (S-2474) was selected as an antiarthritic drug candidate and is now under clinical trials. The structure-activity relationships (SAR) examined and some pharmacological evaluations are described.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Artrite/tratamento farmacológico , Óxidos S-Cíclicos/síntese química , Isoenzimas/farmacologia , Inibidores de Lipoxigenase , Prostaglandina-Endoperóxido Sintases/farmacologia , Tiazóis/síntese química , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite Experimental/tratamento farmacológico , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Óxidos S-Cíclicos/efeitos adversos , Óxidos S-Cíclicos/uso terapêutico , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase/síntese química , Inibidores de Ciclo-Oxigenase/uso terapêutico , Dinoprostona/antagonistas & inibidores , Dinoprostona/biossíntese , Edema/induzido quimicamente , Edema/tratamento farmacológico , Feminino , Mucosa Gástrica/efeitos dos fármacos , Humanos , Interleucina-1/antagonistas & inibidores , Interleucina-1/farmacologia , Leucotrieno B4/antagonistas & inibidores , Leucotrieno B4/biossíntese , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/uso terapêutico , Masculino , Proteínas de Membrana , Ratos , Ratos Endogâmicos Lew , Relação Estrutura-Atividade , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/metabolismo , Tiazóis/efeitos adversos , Tiazóis/uso terapêuticoAssuntos
Anti-Inflamatórios não Esteroides/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Norbornanos/farmacologia , Prostaglandina D2/metabolismo , Receptores Imunológicos , Receptores de Prostaglandina/administração & dosagem , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/química , Plaquetas/efeitos dos fármacos , Compostos Bicíclicos com Pontes/administração & dosagem , Compostos Bicíclicos com Pontes/química , Cobaias , Humanos , Norbornanos/administração & dosagem , Norbornanos/química , Receptores de Prostaglandina/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
New platelet activating factor (PAF) antagonists, 3 were synthesized by replacing the charged phosphate and trimethylammonium moieties with sulfonamide and heterocyclic quaternary ammonium functionalities, respectively (PAF-sulfonamide isosteres). Darmstoff phosphatidic acid analogues of this class (Darmstoff-sulfonamide isosteres), 6 were also synthesized. The activity of these compounds as PAF antagonists was evaluated from their in vitro inhibitory effect on PAF-induced platelet aggregation in rabbit platelet-rich plasma. Among the compounds tested, some of the 2-methoxypropane derivatives with an octadecylcarbamoyloxy or octadecylcarbamoylthio side chain at the 1-position and a propylsulfonamide function bearing a terminal polar substituent such as a quaternary quinolinium or substituted quinolinium group at the 3-position were found to be the most potent (IC50 = 0.3-0.6 microM).
Assuntos
Fator de Ativação de Plaquetas/antagonistas & inibidores , Inibidores da Agregação Plaquetária/síntese química , Sulfonamidas/síntese química , Animais , Técnicas In Vitro , Isomerismo , Masculino , Fator de Ativação de Plaquetas/química , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Coelhos , Relação Estrutura-Atividade , Sulfonamidas/farmacologiaRESUMO
In a continuing effort to obtain more potent platelet activating factor (PAF) antagonists, we tried to synthesize a series of PAF-sulfonamide isosteres in which the substituent at the 2-position was modified to an acetoxy equivalent other than the methoxy group. These modifications produced highly active PAF antagonists. Compound 3-[2-(5-methyl-2H-tetrazol-2-yl)-3-(octadecylcarbamoyloxy) propylaminosulfonyl]propylquinolinium iodide (52) showed the most potent activity in the in vitro inhibitory effect on PAF-induced platelet aggregation in rabbit platelet-rich plasma (IC50 = 125 nM) and also in the in vivo protective effect on PAF-induced lethality in mice, with prolonged duration of action. Optically active enantiomers of this compound were synthesized and the (S)-(-)-isomer (IC50 = 87 nM) was found to be three times more potent that the (R)-(+)-isomer (IC50 = 289 nM), clearly exemplifying the enantioselectivity in the PAF-antagonist action of this novel compound.
Assuntos
Glicerol/química , Fator de Ativação de Plaquetas/antagonistas & inibidores , Sulfonamidas/síntese química , Animais , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos , Fator de Ativação de Plaquetas/química , Fator de Ativação de Plaquetas/toxicidade , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Coelhos , Relação Estrutura-Atividade , Sulfonamidas/farmacologiaRESUMO
Thromboxane A2 receptor antagonists 11a, 15a, 26a, 30a, 34a, 36a, 46a, 52a, 61a, 72a, and 82a, which contain 6-oxabicyclo[3.1.0]hexane, 6-thiabicyclo[3.1.0]hexane, bicyclo[3.1.0]hexane, or 6,6-dimethylbicyclo[3.1.0]hexane ring systems with heptenoic and (phenylsulfonyl)amino side chains, and their corresponding sodium salts and methyl esters were synthesized. This study then examined the inhibitory effects of their sodium salts for the platelet aggregation induced by arachidonic acid with rabbit platelet-rich plasma and platelet aggregation induced by collagen with rat washed platelets.
