RESUMO
Herein we report the synthesis and activity of a novel class of HDAC inhibitors based on 2, 3-diphenyl acrylic acid derivatives. The compounds in this series have shown to be potent HDAC inhibitors possessing significant antiproliferative activity. Further compounds in this series were subjected to metabolic stability in human liver microsomes (HLM), mouse liver microsomes (MLM), and exhibits promising stability in both. These efforts culminated with the identification of a developmental candidate (5a), which displayed desirable PK/PD relationships, significant efficacy in the xenograft models and attractive ADME profiles.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Cinamatos/farmacologia , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/farmacologia , Estilbenos/administração & dosagem , Estilbenos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Administração Oral , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cinamatos/administração & dosagem , Cinamatos/química , Relação Dose-Resposta a Droga , Inibidores de Histona Desacetilases/química , Histona Desacetilases/metabolismo , Humanos , Camundongos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Estilbenos/química , Relação Estrutura-AtividadeRESUMO
Herein, we report the development of highly potent HDAC inhibitors for the treatment of cancer. A series of adamantane and nor-adamantane based HDAC inhibitors were designed, synthesized and screened for the inhibitory activity of HDAC. A number of compounds exhibited GI50 of 10-100 nM in human HCT116, NCI-H460 and U251 cancer cells, in vitro. Compound 32 displays efficacy in human tumour animal xenograft model.
Assuntos
Adamantano/análogos & derivados , Adamantano/química , Adamantano/síntese química , Antineoplásicos/química , Inibidores de Histona Desacetilases/química , Histona Desacetilases/química , Adamantano/uso terapêutico , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Camundongos SCID , Relação Estrutura-Atividade , Transplante HeterólogoRESUMO
A series of novel dibenzo[b,d]furan mono-carboxylic acid derivatives were synthesized, characterized and evaluated for their ability to inhibit Protein Tyrosine Phosphatase 1B (PTP1B) in vitro in order to use them as potential anti-diabetic agents. Structure-activity relationship study led to the identification of potent compound 5 E which inhibited PTP1B with IC(50) value of 82+/-0.43 nM. Compound 5 E was screened in vivo as drug candidate for anti-diabetic activity using rosiglitazone maleate as the standard. Compound 5 E showed significant reduction in body weight, fed-state whole blood glucose (WBG), fasting WBG, plasma glucose and plasma cholesterol levels and non-significant reduction in fasting plasma triglyceride levels in ob/ob mice.
Assuntos
Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacologia , Furanos/química , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Ácidos Carboxílicos/química , Domínio Catalítico , Colesterol/sangue , Descoberta de Drogas , Hipoglicemiantes/química , Concentração Inibidora 50 , Masculino , Camundongos , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 1/química , Especificidade por Substrato , Triglicerídeos/sangueRESUMO
A series of novel isochroman mono-carboxylic acid derivatives were synthesized, characterized and evaluated for their ability to inhibit protein tyrosine phosphatase 1B (PTP1B) in vitro in order to use them as potential anti-diabetic agents. Analysis of structure-activity relationships led to the identification of potent compound 4n which inhibited PTP1B with IC(50) value of 51.63+/-0.91 nM. In general, high potency was associated with a dithiolane ring with a spacer of five carbons to the isochroman ring. Compound 4n has been selected for in vivo evaluation as drug candidate for anti-diabetic activity.