RESUMO
A novel series of barbituric acid derivatives were identified as selective inhibitors of alpha4beta7 MAdCAM (mucosal addressin cell adhesion molecule-1) interactions via a high throughput screening exercise. These inhibitors were optimized to submicromolar potencies in whole cell adhesion assays, retaining their selectivity over alpha4beta1 VCAM.
Assuntos
Barbitúricos/farmacologia , Adesão Celular/efeitos dos fármacos , Integrinas/antagonistas & inibidores , Mucoproteínas/antagonistas & inibidores , Animais , Barbitúricos/síntese química , Sítios de Ligação , Adesão Celular/fisiologia , Moléculas de Adesão Celular , Imunoglobulinas/metabolismo , Integrina alfa4beta1/metabolismo , Integrinas/metabolismo , Camundongos , Modelos Químicos , Mucoproteínas/metabolismo , Relação Estrutura-Atividade , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
Glucocorticoids (GCs) are commonly used to treat inflammatory disease; unfortunately, the long-term use of these steroids leads to a large number of debilitating side effects. The antiinflammatory effects of GCs are a result of GC receptor (GR)-mediated inhibition of expression of proinflammatory genes as well as GR-mediated activation of antiinflammatory genes. Similarly, side effects are most likely due to both activated and repressed GR target genes in affected tissues. An as yet unachieved pharmaceutical goal is the development of a compound capable of separating detrimental side effects from antiinflammatory activity. We describe the discovery and characterization of AL-438, a GR ligand that exhibits an altered gene regulation profile, able to repress and activate only a subset of the genes normally regulated by GCs. When tested in vivo, AL-438 retains full antiinflammatory efficacy and potency comparable to steroids but its negative effects on bone metabolism and glucose control are reduced at equivalently antiinflammatory doses. The mechanism underlying this selective in vitro and in vivo activity may be the result of differential cofactor recruitment in response to ligand. AL-438 reduces the interaction between GR and peroxisomal proliferator-activated receptor gamma coactivator-1, a cofactor critical for steroid-mediated glucose up-regulation, while maintaining normal interactions with GR-interacting protein 1. This compound serves as a prototype for a unique, nonsteroidal alternative to conventional GCs in treating inflammatory disease.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Benzopiranos/farmacologia , Quinolinas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/metabolismo , Artrite Experimental/tratamento farmacológico , Benzopiranos/efeitos adversos , Benzopiranos/metabolismo , Osso e Ossos/efeitos dos fármacos , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos/métodos , Edema/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Glucocorticoides/farmacologia , Humanos , Inflamação/tratamento farmacológico , Masculino , Coativador 2 de Receptor Nuclear , Prednisolona/metabolismo , Prednisolona/farmacologia , Quinolinas/efeitos adversos , Quinolinas/metabolismo , Ratos , Ratos Sprague-Dawley , Tíbia/anatomia & histologia , Tíbia/efeitos dos fármacos , Fatores de Transcrição/efeitos dos fármacos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
The synthesis and biological activities of rapamycin (I) analogs modified at the C-40 position are reported. Emphasis placed on compounds that potentially have an improved safety profile on account of their shorter in vivo half-life when compared with rapamycin.
Assuntos
Antirreumáticos/química , Antirreumáticos/farmacocinética , Artrite Reumatoide/metabolismo , Sirolimo/análogos & derivados , Animais , Antirreumáticos/toxicidade , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/tratamento farmacológico , Masculino , Radiografia , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-DawleyRESUMO
Interleukin-8 modulation is implicated in many inflammatory and cancer diseases. Starting from a mass-screening hit, the synthesis and structure-activity relationship of 2-amino-3-heteroarylquinoxalines as non-peptide, small molecule interleukine-8 receptor antagonists have been developed. The optimized derivatives, PD 0210293 (13y) and PD 0220245 (13r), show inhibition of both IL-8 receptor binding and IL-8-mediated neutrophil chemotaxis.