RESUMO
A series of 5-ureidobenzofuranones was discovered as potent and selective inhibitors of mTOR with good cellular activity. Molecular modeling studies revealed several hydrogen bond interactions of the ureido group with the enzyme at the ATP-binding site. Furthermore, modeling showed that the ureido group is best situated at C-5 of the benzofuranone. Syntheses of 4-ureido and 5-ureidobenzofuranones are presented.
Assuntos
Trifosfato de Adenosina/metabolismo , Benzofuranos/química , Benzofuranos/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Classe Ib de Fosfatidilinositol 3-Quinase , Cristalografia por Raios X , Humanos , Ligação de Hidrogênio , Peptídeos e Proteínas de Sinalização Intracelular/química , Isoenzimas/química , Modelos Moleculares , Fosfatidilinositol 3-Quinases/química , Proteínas Serina-Treonina Quinases/química , Sirolimo , Homologia Estrutural de Proteína , Serina-Treonina Quinases TORRESUMO
We discovered 2-(4-substituted-pyrrolo[2,3-b]pyridin-3-yl)methylene-4-hydroxybenzofuran-3(2H)-ones as potent and selective ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR). Since phenolic OH groups pose metabolic liability, one of the two hydroxyl groups was selectively removed. The SAR data showed the structural features necessary for subnanomolar inhibitory activity against mTOR kinase as well as selectivity over PI3Kalpha. An X-ray co-crystal structure of one inhibitor with the mTOR-related PI3Kgamma revealed the key hydrogen bonding interactions.
Assuntos
Benzofuranos/química , Benzofuranos/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Cristalografia por Raios X , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Nus , Microssomos/metabolismo , Modelos Moleculares , Neoplasias/tratamento farmacológico , Fosfatidilinositol 3-Quinases/química , Fosfatidilinositol 3-Quinases/metabolismo , Relação Estrutura-Atividade , Serina-Treonina Quinases TORRESUMO
Potent and selective TACE and MMP inhibitors utilizing the diazepine and thiazepine ring systems were synthesized and evaluated for biological activity in in vitro and in vivo models of TNF-alpha release. Oral activity in the mouse LPS model of TNF-alpha release was seen. Efficacy in the mouse collagen induced arthritis model was achieved with diazepine 20.
Assuntos
Azepinas/química , Azepinas/farmacologia , Inibidores de Metaloproteinases de Matriz , Metaloendopeptidases/antagonistas & inibidores , Proteínas ADAM , Proteína ADAM17 , Animais , Azepinas/síntese química , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Químicos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A series of benzodiazepine MMP/TACE inhibitors bearing polar moieties has been synthesized in an effort to optimize inhibitory activity against LPS-stimulated TNF production in human monocytes and oral activity in a murine LPS model.