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1.
Bioorg Med Chem Lett ; 22(12): 4163-8, 2012 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-22607682

RESUMO

High throughput screening to identify inhibitors of the mTOR kinase revealed sulfonyl-morpholino-pyrimidine 1 as an attractive start point. The compound displayed good physicochemical properties and selectivity over related kinases such as PI3Kα. Library preparation of related analogs allowed the establishment of additional SAR understanding and in particular the requirement for a key hydrogen bond donor motif at the 4-position of the phenyl ring in compounds such as indole 19. Isosteric replacement of the indole functionality led to the identification of urea compounds such as 32 that show good levels of mTOR inhibition in both enzyme and cellular assays.


Assuntos
Antineoplásicos/síntese química , Morfolinas/síntese química , Inibidores de Proteínas Quinases/síntese química , Pirimidinas/síntese química , Sulfonas/síntese química , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Disponibilidade Biológica , Linhagem Celular Tumoral , Humanos , Ligação de Hidrogênio , Indóis/química , Concentração Inibidora 50 , Morfolinas/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Ratos , Relação Estrutura-Atividade , Sulfonas/farmacologia , Serina-Treonina Quinases TOR/química , Ureia/análogos & derivados , Ureia/química
2.
Bioorg Med Chem Lett ; 21(18): 5224-9, 2011 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-21835616

RESUMO

A directed screen of a relatively small number of compounds, selected for kinase ATP pocket binding potential, yielded a novel series of hit compounds (1). Hit explosion on two binding residues identified compounds 27 and 43 as the best leads for an optimization program having reduced secondary metabolism, as measured by in vitro rat hepatocytes incubation, leading to oral bio-availability. Structure-activity relationships and molecular modeling have suggested a binding mode for the most potent inhibitor 12.


Assuntos
Anilidas/farmacologia , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Anilidas/síntese química , Anilidas/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-met/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade
3.
J Mol Biol ; 319(1): 173-81, 2002 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-12051944

RESUMO

Matrix metalloproteinases (MMPs) and their inhibitors are important in connective tissue re-modelling in diseases of the cardiovascular system, such as atherosclerosis. Various members of the MMP family have been shown to be expressed in atherosclerotic lesions, but MMP9 is consistently seen in inflammatory atherosclerotic lesions. MMP9 over-expression is implicated in the vascular re-modelling events preceding plaque rupture (the most common cause of acute myocardial infarction). Reduced MMP9 activity, either by genetic manipulation or through pharmacological intervention, has an impact on ventricular re-modelling following infarction. MMP9 activity may therefore represent a key mechanism in the pathogenesis of heart failure. We have determined the crystal structure, at 2.3 A resolution, of the catalytic domain of human MMP9 bound to a peptidic reverse hydroxamate inhibitor as well as the complex of the same inhibitor bound to an active-site mutant (E402Q) at 2.1 A resolution. MMP9 adopts the typical MMP fold. The catalytic centre is composed of the active-site zinc ion, co-ordinated by three histidine residues (401, 405 and 411) and the essential glutamic acid residue (402). The main differences between the catalytic domains of various MMPs occur in the S1' subsite or selectivity pocket. The S1' specificity site in MMP9 is perhaps best described as a tunnel leading toward solvent, as in MMP2 and MMP13, as opposed to the smaller pocket found in fibroblast collagenase and matrilysin. The present structure enables us to aid the design of potent and specific inhibitors for this important cardiovascular disease target.


Assuntos
Inibidores Enzimáticos/metabolismo , Ácidos Hidroxâmicos/metabolismo , Ácidos Hidroxâmicos/farmacologia , Metaloproteinase 9 da Matriz/química , Inibidores de Metaloproteinases de Matriz , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Inibidores Enzimáticos/farmacologia , Humanos , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Eletricidade Estática
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