RESUMO
A series of sulfonamide-containing 1,5-diarylpyrazole derivatives were prepared and evaluated for their ability to block cyclooxygenase-2 (COX-2) in vitro and in vivo. Extensive structure-activity relationship (SAR) work was carried out within this series, and a number of potent and selective inhibitors of COX-2 were identified. Since an early structural lead (1f, SC-236) exhibited an unacceptably long plasma half-life, a number of pyrazole analogs containing potential metabolic sites were evaluated further in vivo in an effort to identify compounds with acceptable pharmacokinetic profiles. This work led to the identification of 1i (4-[5-(4-methylphenyl)-3-(trifluoromethyl)- H-pyrazol-1-yl]benzenesulfonamide, SC-58635, celecoxib), which is currently in phase III clinical trials for the treatment of rheumatoid arthritis and osteoarthritis.
Assuntos
Inibidores de Ciclo-Oxigenase/síntese química , Inibidores de Ciclo-Oxigenase/farmacologia , Isoenzimas/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Animais , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Carragenina/farmacologia , Celecoxib , Ciclo-Oxigenase 1 , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase/química , Inibidores de Ciclo-Oxigenase/farmacocinética , Hiperalgesia/tratamento farmacológico , Espectroscopia de Ressonância Magnética , Masculino , Proteínas de Membrana , Estrutura Molecular , Osteoartrite/tratamento farmacológico , Pirazóis , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Leukotriene B(4) (LTB(4)) is a pro-inflammatory mediator that has been implicated in the pathogenesis of a number of diseases including inflammatory bowel disease (IBD) and psoriasis. Since the action of LTA(4) hydrolase is the rate-limiting step for LTB(4) production, this enzyme represents an attractive pharmacological target for the suppression of LTB(4) production. From an in-house screening program, SC-22716 (1, 1-[2-(4-phenylphenoxy)ethyl]pyrrolidine) was identified as a potent inhibitor of LTA(4) hydrolase. Structure-activity relationship (SAR) studies around this structural class resulted in the identification of a number of novel, potent inhibitors of LTA(4) hydrolase, several of which demonstrated good oral activity in a mouse ex vivo whole blood assay.
Assuntos
Inibidores Enzimáticos/síntese química , Epóxido Hidrolases/antagonistas & inibidores , Pirrolidinas/síntese química , Administração Oral , Animais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Técnicas In Vitro , Leucotrieno B4/biossíntese , Leucotrieno B4/sangue , Masculino , Camundongos , Pirrolidinas/química , Pirrolidinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Leukotriene B4 (LTB4) and 12(R)-hydroxyeicosatetraenoic acid [12(R)-HETE] are proinflammatory products of arachidonic acid metabolism that have been implicated as mediators in a number of inflammatory diseases. When injected intradermally into the guinea pig. LTB4 and 12(R)-HETE elicit a dose-dependent migration (chemotaxis) of neutrophils (PMNs) into the injection sites as assessed by the presence of a neutrophil marker enzyme myeloperoxidase. SC-41930 (7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxyl]-3,4-dihy dro-8-propyl-2H - 1-benzopyran-2-carboxylic acid), a first-generation LTB4 receptor antagonist, inhibited the chemotactic actions of LTB4 when given orally with an ED50 value of 1.7 mg/kg. The second-generation LTB4 receptor antagonist, SC-53228 [(+)-(S)-7-(3-(2-(cyclopropylmethyl)-3-methoxy-4- [(methylamino)carbonyl]phenoxy)propoxy)-3,4-dihydro-8-propyl-2H-1- benzopyran-2-propanoic acid], inhibited LTB4-induced chemotaxis when given intragastrically with an ED50 value of 0.07 mg/kg. Furthermore, SC-53228 inhibited 12(R)-HETE-induced granulocyte chemotaxis with an oral ED50 value of 5.8 mg/kg. When dosed orally over a range of 0.03-100 mg/kg, SC-53228 gave Cmax plasma concentrations of 0.015-41.1 micrograms/ml. SC-53228 inhibited LTB4-primed membrane depolarization of human neutrophils with an IC50 value of 34 nM. As a potent LTB4 receptor antagonist, SC-53228 may well have application in the medical management of disease states such as asthma, rheumatoid arthritis, inflammatory bowel disease, contact dermatitis, and psoriasis, in which LTB4 and/or 12(R)-HETE are implicated as inflammatory mediators.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Benzamidas/farmacologia , Benzopiranos/farmacologia , Quimiotaxia de Leucócito/efeitos dos fármacos , Ácidos Hidroxieicosatetraenoicos/farmacologia , Leucotrieno B4/farmacologia , Receptores do Leucotrieno B4/antagonistas & inibidores , Pele/efeitos dos fármacos , Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Benzamidas/administração & dosagem , Benzopiranos/administração & dosagem , Biomarcadores , Granulócitos/efeitos dos fármacos , Cobaias , Ácidos Hidroxieicosatetraenoicos/administração & dosagem , Injeções Intradérmicas , Leucotrieno B4/administração & dosagem , Masculino , Potenciais da Membrana/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Neutrófilos/enzimologia , Peroxidase/análise , Receptores do Leucotrieno B4/fisiologia , Pele/imunologia , Pele/patologiaRESUMO
SC-41930, 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-3,4- dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid, is a selective, orally active, LTB4 receptor antagonist currently in clinical trials for psoriasis and ulcerative colitis. Exhaustive SAR studies found a potential backup compound, SC-50605, which was 7-16 times more potent than SC-41930 in LTB4 receptor binding, chemotaxis and degranulation assays. SC-50605 also inhibited LTB4-induced intradermal chemotaxis in cavine skin at an oral dose of 0.10 mg/kg and displayed good activity in animal models of colitis and epidermal inflammation both orally and topically.