RESUMO
Leukotrienes (LT's) are known to play a physiological role in inflammatory immune response. Leukotriene A(4) hydrolase (LTA(4)H) is a cystolic enzyme that stereospecifically catalyzes the transformation of LTA(4) to LTB(4). LTB(4) is a known pro-inflammatory mediator. This paper describes the identification and synthesis of substituted benzofurans as LTH(4)H inhibitors. The benzofuran series demonstrated reduced mouse and human whole blood LTB(4) levels in vitro and led to the identification one analog for advanced profiling. Benzofuran 28 showed dose responsive target engagement and provides a useful tool to explore a LTA(4)H inhibitor for the treatment of inflammatory diseases, such as asthma and inflammatory bowel disease (IBD).
Assuntos
Benzofuranos/química , Inibidores Enzimáticos/química , Epóxido Hidrolases/antagonistas & inibidores , Animais , Benzofuranos/farmacologia , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Ratos , Ratos Sprague-DawleyRESUMO
Previously, benzthiazole containing LTA(4)H inhibitors were discovered that were potent (1-3), but were associated with the potential for a hERG liability. Utilizing medicinal chemistry first principles (e.g., introducing rigidity, lowering cLogD) a new benzthiazole series was designed, congeners of 1-3, which led to compounds 7a, 7c, 12a-d which exhibited LTA(4)H IC(50)=3-6 nM and hERG Dofetilide Binding IC(50)=8.9-> >10 µM.
Assuntos
Compostos Aza/farmacologia , Benzotiazóis/farmacologia , Inibidores Enzimáticos/farmacologia , Epóxido Hidrolases/antagonistas & inibidores , Animais , Compostos Aza/síntese química , Compostos Aza/química , Benzotiazóis/síntese química , Benzotiazóis/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Epóxido Hidrolases/metabolismo , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Humanos , Camundongos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A novel class of tetrahydropyrido-pyrazole thioether amines that display potency against human Cathepsin S have been previously reported. Here, further SAR investigations of the P3, P4, and P5 regions are described. In particular, 4-fluoropiperidine is identified as a competent P3 binding element when utilized in conjunction with a (S)-2-hydroxypropyl linker-containing P5 moiety and oxamide or sulfonamide P4 substitution.
Assuntos
Catepsinas/antagonistas & inibidores , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Sulfetos/química , Sulfetos/farmacologia , Catepsinas/metabolismo , Linhagem Celular , Humanos , Relação Estrutura-AtividadeRESUMO
A series of tetrahydropyrido-pyrazole cathepsin S (CatS) inhibitors with thioether acetamide functional groups were prepared with the goal of improving upon the cellular activity of amidoethylthioethers. This Letter describes altered amide connectivity, in conjunction with changes to other binding elements, resulting in improved potency, as well as increased knowledge of the relationship between this chemotype and human CatS activity.
Assuntos
Acetamidas/farmacologia , Catepsinas/antagonistas & inibidores , Catepsinas/metabolismo , Inibidores de Proteases/farmacologia , Pirazóis/farmacologia , Sulfetos/farmacologia , Acetamidas/química , Catepsinas/química , Linhagem Celular , Humanos , Modelos Moleculares , Inibidores de Proteases/química , Pirazóis/química , Relação Estrutura-Atividade , Sulfetos/químicaRESUMO
Previous research on histamine H(3) antagonists has led to the development of a pharmacophore model consisting of a central phenyl core flanked by two alkylamine groups. Recent investigation of the replacement of the central phenyl core with heteroaromatic fragments resulted in the preparation of novel 3,5-, 3,6- and 3,7-substituted indole and 3,5-substituted benzothiophene analogs that demonstrate good to excellent hH(3) affinities. Select analogs were profiled in a rat pharmacokinetic model.
Assuntos
Antagonistas dos Receptores Histamínicos H3/síntese química , Antagonistas dos Receptores Histamínicos H3/farmacologia , Indóis/síntese química , Indóis/farmacologia , Tiofenos/síntese química , Tiofenos/farmacologia , Animais , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H3/farmacocinética , Indicadores e Reagentes , Indóis/farmacocinética , Isomerismo , Modelos Moleculares , Ratos , Relação Estrutura-Atividade , Tiofenos/farmacocinéticaRESUMO
A series of pyrazole-based thioethers were prepared and found to be potent cathepsin S inhibitors. A crystal structure of 13 suggests that the thioether moiety may bind to the S3 pocket of the enzyme. Additional optimization led to the discovery of aminoethylthioethers with improved enzymatic activity and submicromolar cellular potency.
Assuntos
Catepsinas/antagonistas & inibidores , Catepsinas/metabolismo , Inibidores de Proteases/farmacologia , Pirazóis/farmacologia , Sulfetos/farmacologia , Sítios de Ligação , Catepsinas/química , Linhagem Celular , Cristalografia por Raios X , Humanos , Modelos Moleculares , Inibidores de Proteases/química , Pirazóis/química , Relação Estrutura-Atividade , Sulfetos/químicaRESUMO
A series of benzimidazole compounds containing pendant alcohol and amine moieties was found to be active against checkpoint kinase Chk2. These compounds were prepared to examine a potential hydrogen bond interaction with an active site residue and to investigate replacement of a biaryl linker with an aliphatic system in an effort to improve solubility.
Assuntos
Álcoois/química , Aminas/química , Benzimidazóis/química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Álcoois/farmacologia , Aminas/farmacologia , Benzimidazóis/farmacologia , Quinase do Ponto de Checagem 2 , Ligação de Hidrogênio , Inibidores de Proteínas Quinases/farmacologiaRESUMO
INTRODUCTION: Cathepsin S, a lysosomal cysteine protease, plays an important role in antigen presentation. Its inhibition is expected to result in immunosuppression, making this enzyme an attractive target to potentially treat autoimmune and inflammatory diseases. AREAS COVERED: The focus of this review is on patent literature regarding small molecule inhibitors of cathepsin S published from 2004 to April 2010. Different structure classes based on binding strategies (covalent vs non-covalent) are surveyed and listed according to warhead type and research organization. EXPERT OPINION: Although > 40 patent applications have appeared between 2004 and 2010, the decrease in applications focusing on cathepsin S over the past 2 - 3 years may reflect a renewed interest in other cathepsins, especially cathepsin K, for which a small molecule inhibitor is currently in Phase III clinical trials.
Assuntos
Catepsinas/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Animais , Catepsinas/química , Humanos , Patentes como Assunto , Relação Estrutura-Atividade , Fatores de TempoRESUMO
A series of 2-arylbenzimidazoles was synthesized and found to bind with high affinity to the human histamine H(4) receptor. Structure-activity relationships were investigated through library preparation and evaluation as well as traditional medicinal chemistry approaches, leading to the discovery of compounds with single-digit nanomolar affinity for the H(4) receptor.