RESUMO
Small-molecule library screening to find compounds that inhibit TNFalpha-induced, but not interleukin 1beta (IL-1beta)-induced, intercellular adhesion molecule 1 (ICAM-1) expression in lung epithelial cells identified a class of triazoloquinoxalines. These compounds not only inhibited the TNFalpha-induced nuclear factor kappaB (NFkappaB) survival pathway but also blocked death-pathway activation. Such dual activity makes them unique against other known NFkappaB-pathway inhibitors that inhibit only a subset of TNFalpha signals leading to increased TNFalpha-induced cytotoxicity. Interestingly, these compounds inhibited association of TNFalpha receptor (TNFalphaR) I with TNFalphaR-associated death domain protein (TRADD) and receptor interacting protein 1 (RIP1), the initial intracellular signaling event following TNFalpha stimulation. Further study showed that they blocked ligand-dependent internalization of the TNFalpha-TNFalphaR complex, thereby inhibiting most of the TNFalpha-induced cellular responses. Thus, compounds with a triazoloquinoxaline scaffold could be a valuable tool to investigate small molecule-based anti-TNFalpha therapies.
Assuntos
Apoptose/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Molécula 1 de Adesão Intercelular/metabolismo , Quinoxalinas/farmacologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Proteína de Domínio de Morte Associada a Receptor de TNF/metabolismo , Triazóis/farmacologia , Fator de Necrose Tumoral alfa , Apoptose/fisiologia , Membrana Celular/química , Membrana Celular/metabolismo , Células Epiteliais/citologia , Células Epiteliais/patologia , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/fisiologia , Molécula 1 de Adesão Intercelular/genética , Pulmão/citologia , Pulmão/patologia , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Bibliotecas de Moléculas Pequenas , Proteína de Domínio de Morte Associada a Receptor de TNF/genéticaRESUMO
The azetidinone LY307174 (1) was identified as a screening lead for the vasopressin V1a receptor (IC50 45 nM at the human V1a receptor) based on molecular similarity to ketoconazole (2), a known antagonist of the luteinizing hormone releasing hormone receptor. Structure-activity relationships for the series were explored to optimize receptor affinity and pharmacokinetic properties, resulting in compounds with Ki values <1nM and brain levels after oral dosing approximately 100-fold higher than receptor affinities.
Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos , Azetidinas/farmacologia , Animais , Azetidinas/sangue , Azetidinas/farmacocinética , Encéfalo/metabolismo , Células CHO , Cricetinae , Cricetulus , Cães , Humanos , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Ratos , Espectrometria de Massas de Bombardeamento Rápido de ÁtomosRESUMO
Glycopeptide antibiotics were synthesized via the PyBOP mediated condensation of aliphatic, heterocyclic and aromatic amines with the C-terminus of vancomycin, LY264826 (A82846B) and semi-synthetic derivatives of these natural products. Amides of LY264826 and vancomycin demonstrated excellent activity against staphylococci and streptococci as compared to the parent natural product. However, the amides of N-alkylated LY264826 and N-alkylated vancomycin were active against vancomycin-resistant enterococci as well as other gram-positive pathogens such as Staphylococcus aureus, S. haemolyticus, S. epidermidis and Streptococcus pneumoniae.
