RESUMO
A novel series of N-(3-(6-substituted-aminopyridin-3-yloxy)phenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides targeting TrkA receptor tyrosine kinase was identified. SAR study of the series allowed us to design and synthesize compounds possessing inhibitory activity of TrkA kinase enzyme in the low nanomolar range with low residual activity against c-Met and with no significant activity against VEGFR2.
RESUMO
A novel series of N-(3-fluoro-4-(2-substituted-thieno[3,2-b]pyridin-7-yloxy)phenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamides targeting RON receptor tyrosine kinase was designed and synthesized. SAR study of the series allowed us to identify compounds possessing either inhibitory activity of RON kinase enzyme in the low nanomolar range with low residual activity against the closely related c-Met or potent dual inhibitory activity against RON and c-Met, with no significant activity against VEGFR2 in both cases.
Assuntos
Antineoplásicos/química , Inibidores de Proteínas Quinases/química , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 2 Anéis/química , Compostos Heterocíclicos com 2 Anéis/farmacocinética , Humanos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/metabolismo , Pirazóis/síntese química , Pirazóis/química , Pirazóis/farmacocinética , Ratos , Receptores Proteína Tirosina Quinases/metabolismo , Relação Estrutura-AtividadeRESUMO
A novel series of malonamide-type dual VEGFR2/c-Met inhibitors in which one of the amide bonds was replaced by an amide isostere-a trifluoroethylamine unit, was designed, synthesized, and evaluated for their enzymatic and cellular inhibition of VEGFR2 and c-Met enzymes. Optimization of these molecular entities resulted in identification of potent and selective inhibitors of VEGFR2 enzyme.
Assuntos
Amidas/química , Inibidores de Proteínas Quinases/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Amidas/farmacologia , Técnicas de Cocultura , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/enzimologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/enzimologia , Humanos , Inibidores de Proteínas Quinases/farmacologia , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
A family of thieno[3,2-b]pyridine based small molecule inhibitors of c-Met and VEGFR2 were designed based on lead structure 2. These compounds were shown to have IC(50) values in the low nanomolar range in vitro and were efficacious in human tumor xenograft models in mice in vivo.
Assuntos
Antineoplásicos/química , Malonatos/química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Piridinas/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Administração Oral , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Humanos , Malonatos/síntese química , Malonatos/farmacocinética , Camundongos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Piridinas/síntese química , Piridinas/farmacocinéticaRESUMO
A series of N-(4-(6,7-disubstituted-quinolin-4-yloxy)-3-fluorophenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides targeting c-Met and VEGFR2 tyrosine kinases was designed and synthesized. The compounds were potent against these two enzymes with IC(50) values in the low nanomolar range in vitro, possessed favorable pharmacokinetic profiles and showed high efficacy in vivo in several human tumor xenograft models in mice.
Assuntos
Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of N-(3-fluoro-4-(2-arylthieno[3,2-b]pyridin-7-yloxy)phenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides targeting c-Met and VEGFR2 tyrosine kinases was designed and synthesized. The compounds were potent against these two enzymes with IC(50) values in the low nanomolar range in vitro, possessed favorable pharmacokinetic profiles and showed high efficacy in vivo in several human tumor xenograft models in mice.
Assuntos
Amidas/química , Imidazolidinas/química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-met/administração & dosagem , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Amidas/farmacologia , Animais , Linhagem Celular Tumoral , Células HCT116 , Humanos , Imidazolidinas/farmacologia , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Ratos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
Analogues of the clinical compound MGCD0103 (A) were designed and synthesized. These compounds inhibit recombinant human HDAC1 with IC(50) values in the sub-micromolar range. In human cancer cells growing in culture these compounds induce hyperacetylation of histones, cause expression of the tumor suppressor protein p21(WAF1/CIP1), and inhibit cellular proliferation. Lead molecule of the series, compound 25 is metabolically stable, possesses favorable pharmacokinetic characteristics and is orally active in vivo in different mouse tumor xenograft models.
Assuntos
Benzamidas/farmacologia , Inibidores Enzimáticos/farmacologia , Pirimidinas/farmacologia , Animais , Antineoplásicos/farmacologia , Benzamidas/síntese química , Linhagem Celular Tumoral , Proliferação de Células , Química Farmacêutica/métodos , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores de Histona Desacetilases , Humanos , Concentração Inibidora 50 , Camundongos , Transplante de Neoplasias , Pirimidinas/síntese química , Relação Estrutura-AtividadeRESUMO
The design, synthesis, and biological evaluation of N-(2-aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide 8 (MGCD0103) is described. Compound 8 is an isotype-selective small molecule histone deacetylase (HDAC) inhibitor that selectively inhibits HDACs 1-3 and 11 at submicromolar concentrations in vitro. 8 blocks cancer cell proliferation and induces histone acetylation, p21 (cip/waf1) protein expression, cell-cycle arrest, and apoptosis. 8 is orally bioavailable, has significant antitumor activity in vivo, has entered clinical trials, and shows promise as an anticancer drug.
Assuntos
Benzamidas/farmacologia , Inibidores Enzimáticos/farmacologia , Inibidores de Histona Desacetilases , Pirimidinas/farmacologia , Administração Oral , Animais , Benzamidas/administração & dosagem , Benzamidas/química , Cães , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Humanos , Masculino , Pirimidinas/administração & dosagem , Pirimidinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
The synthesis and biological evaluation of a variety of 4-(heteroarylaminomethyl)-N-(2-aminophenyl)-benzamides and their analogs is described. Some of these compounds were shown to inhibit HDAC1 with IC(50) values below the micromolar range, induce hyperacetylation of histones, upregulate expression of the tumor suppressor p21(WAF1/Cip1), and inhibit proliferation of human cancer cells. In addition, certain compounds of this class were active in several human tumor xenograft models in vivo.
Assuntos
Compostos de Anilina/síntese química , Compostos de Anilina/farmacologia , Benzamidas/síntese química , Benzamidas/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Inibidores de Histona Desacetilases , Compostos de Anilina/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzamidas/química , Mama/citologia , Mama/efeitos dos fármacos , Linhagem Celular , Inibidor de Quinase Dependente de Ciclina p21/biossíntese , Inibidores Enzimáticos/química , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células HCT116 , Histona Desacetilase 1 , Humanos , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacologia , Relação Estrutura-AtividadeRESUMO
Inhibition of histone deacetylases (HDAC) is emerging as a new strategy in human cancer therapy. The synthesis and biological evaluation of a variety of 4-(heteroarylaminomethyl)-N-(2-aminophenyl)-benzamides is presented herein. From the different series bearing a six-membered heteroaromatic ring studied, the s-triazine series showed the best HDAC1 enzyme and in vitro anti-proliferative activities with IC(50) values below micromolar range. Some of these compounds can also significantly reduce tumor growth in human tumor xenograft models in mice.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzamidas/síntese química , Benzamidas/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Inibidores de Histona Desacetilases , Pirimidinas/farmacologia , Triazinas/síntese química , Triazinas/farmacologia , Animais , Antineoplásicos/química , Benzamidas/química , Modelos Animais de Doenças , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Camundongos , Relação Estrutura-Atividade , Triazinas/químicaRESUMO
A variety of N-(2-amino-phenyl)-4-(heteroarylmethyl)-benzamides were designed and synthesized. These compounds were shown to inhibit recombinant human HDAC1 with IC(50) values in the sub-micromolar range. In human cancer cells growing in culture these compounds induced hyperacetylation of histones, induced the expression of the tumor suppressor protein p21(WAF1/Cip1), and inhibited cellular proliferation. Certain compounds of this class also showed in vivo activity in various human tumor xenograft models in mice.
Assuntos
Benzamidas/química , Benzamidas/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores de Histona Desacetilases , Aminação , Animais , Sítios de Ligação , Linhagem Celular , Histona Desacetilases/química , Histona Desacetilases/metabolismo , Humanos , Metilação , Camundongos , Modelos Moleculares , Estrutura Molecular , Niacina/farmacologia , Relação Estrutura-Atividade , Ureia/química , Vasodilatação/efeitos dos fármacos , ortoaminobenzoatos/químicaRESUMO
Inhibition of histone deacetylases (HDACs) is emerging as a new strategy in human cancer therapy. Novel 2-aminophenyl benzamides and acrylamides, that can inhibit human HDAC enzymes and induce hyperacetylation of histones in human cancer cells, have been designed and synthesized. These compounds selectively inhibit proliferation and cause cell cycle arrest in various human cancer cells but not in normal cells. The growth inhibition of 2-aminophenyl benzamides and acrylamides against human cancer cells in vitro is reversible and is dependent on the induction of histone acetylation. Compounds of this class can significantly reduce tumor growth in human tumor xenograft models.