RESUMO
In this manuscript, we report the discovery of the substituted 2-trifluoromethyl-2H-benzopyran-3-carboxylic acids as a novel series of potent and selective cyclooxygenase-2 (COX-2) inhibitors. 5c-(S) (SD-8381) was advanced into clinical studies due to its superior in vivo potency. The high plasma protein binding (>99% bound) of 5c-(S) has resulted in a surprisingly long human half life t(1/2)=360 h.
Assuntos
Benzopiranos/química , Benzopiranos/farmacocinética , Inibidores de Ciclo-Oxigenase 2/química , Proteínas Sanguíneas/metabolismo , Ácidos Carboxílicos , Inibidores de Ciclo-Oxigenase 2/farmacocinética , Meia-Vida , Humanos , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
In this Letter, we provide the structure-activity relationships, optimization of design, testing criteria, and human half-life data for a series of selective COX-2 inhibitors. During the course of our structure-based drug design efforts, we discovered two distinct binding modes within the COX-2 active site for differently substituted members of this class. The challenge of a undesirably long human half-life for the first clinical candidate 1t(1/2)=360 h was addressed by multiple strategies, leading to the discovery of 29b-(S) (SC-75416) with t(1/2)=34 h.
Assuntos
Benzopiranos/química , Benzopiranos/farmacocinética , Inibidores de Ciclo-Oxigenase 2/farmacocinética , Sítios de Ligação , Domínio Catalítico , Inibidores de Ciclo-Oxigenase 2/química , Meia-Vida , Humanos , Relação Estrutura-AtividadeRESUMO
A series of pyrazole inhibitors of p38 mitogen-activated protein (MAP) kinase were designed using a binding model based on the crystal structure of 1 (SC-102) bound to p38 enzyme. New chemistry using dithietanes was developed to assemble nitrogen-linked substituents at the 5-position of pyrazoles. Calculated log D was used in tandem with structure-based design to guide medicinal chemistry strategy and improve the in vivo activity of a series of molecules. The crystal structure of an optimized inhibitor, 4 (SC-806), in complex with p38 enzyme was obtained to confirm the hypothesis that the addition of a basic nitrogen to the molecule induces an interaction with Asp112 of p38 alpha. A compound identified from this series was efficacious in an animal model of rheumatic disease.
Assuntos
Antirreumáticos/síntese química , Piperazinas/síntese química , Pirazóis/síntese química , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Antirreumáticos/química , Antirreumáticos/farmacologia , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Colágeno , Cristalografia por Raios X , Masculino , Camundongos , Camundongos Endogâmicos DBA , Modelos Moleculares , Piperazinas/química , Piperazinas/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Ratos , Ratos Endogâmicos Lew , Relação Estrutura-Atividade , Proteínas Quinases p38 Ativadas por Mitógeno/químicaRESUMO
UNLABELLED: In this article, we describe the radiosynthesis and evaluation of 18F-labeled cyclooxygenase (COX) inhibitors. 18F-SC63217 is selective to COX-1 and has a COX-1 inhibitory concentration of 50% (IC(50)) < 10 nmol/L and a COX-2 IC(50) > 100 micromol/L. 18F-SC58125 has IC(50) values of >100 micromol/L (COX-1) and <86 nmol/L (COX-2). METHODS: SC63217 and SC58125 were both labeled with 18F by nucleophilic displacement of a trimethylammonium triflate salt using a dedicated microwave cavity. Each compound was evaluated in vitro using a murine macrophage cell line (J774). COX-2 was stimulated in these cells by treatment with lipopolysaccharide and interferon-gamma. Both radiotracers were further investigated in vivo using rat biodistribution techniques. Brain uptake of the COX-2 inhibitor, 18F-SC58125, was further investigated by brain PET of a baboon. RESULTS: The in vitro studies showed that uptake of 18F-SC58125 was increased in stimulated cells and was totally inhibited by the addition of nonradioactive SC58125. In contrast, no increase in uptake was seen for 18F-SC63217. In the biodistribution experiments, 18F-SC63217 showed much higher uptake in the small intestine (an organ known to express high levels of COX-1) than did 18F-SC58125. Higher levels of 18F-SC58125 were observed in the kidney, an organ known to contain high levels of COX-2 rather than COX-1. 18F-SC58125 was retained in brain tissue. PET images of the baboon showed no regional distribution of the radiotracer in the brain. CONCLUSION: We have developed a radiosynthetic route that can yield 18F-labeled selective inhibitors of COX-1 or COX-2. Both compounds have been fully characterized in vitro and in vivo. Our results indicate that 18F-SC58125 has potential as a marker of COX-2 activity but that, because of high nonspecific binding, 18F-SC63217 was not a good choice as a marker of COX-1.
Assuntos
Inibidores de Ciclo-Oxigenase , Radioisótopos de Flúor , Pirazóis/síntese química , Animais , Linhagem Celular , Inibidores de Ciclo-Oxigenase/síntese química , Feminino , Técnicas In Vitro , Marcação por Isótopo , Camundongos , Papio , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual , Tomografia Computadorizada de EmissãoRESUMO
Zileuton, a redox and iron chelator 5-lipoxygenase (5-LOX) inhibitor and, leukotriene receptor antagonists are presently used clinically in the long term treatment of asthma. Recent data implicate 5-LOX pathway in pain signaling. We report 5-LOX expression in the central nervous system (CNS) and analyze the pain efficacy of a new class of non redox, non iron chelating 5-LOX inhibitor. CJ-13610, 4-(3-(4-(2-methyl-1H-imidazol-1-yl) phenylthio) phenyl)-tetrahydro-2H-pyran-4-carboxamide, demonstrated antihyperalgesic activity in inflammatory pain models including the acute carrageenan model and the chronic inflammatory model using complete Freund's adjuvant. Following complete Freund's adjuvant stimulus leukotrieneB(4) concentration in the brain was elevated (9+/-1 ng/g, mean+/-S.E.M.) by about 3 times that of the control group (3+/-0.11, mean+/-S.E.M.). Hyperalgesia and leukotrieneB(4) concentration were both reversed following CJ-13610 treatment. Furthermore, we demonstrate CJ-13610 efficacy against osteoarthritis like pain using the rat medial meniscal transection model. CJ-13610 at oral doses of 0.6, 2 and 6 mg/kg/day reversed two modalities of pain in this model; tactile allodynia and weight bearing differential. Taken together, these data suggest that 5-LOX pathway and the leukotriene products are important mediators of pain.