Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 33
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Medchemcomm ; 8(4): 725-729, 2017 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30108791

RESUMO

Recently, our research group reported the identification of prodrug amino-alcohol 2 as a potent and efficacious S1P1 receptor modulator. This molecule is differentiated preclinically over the marketed drug fingolimod (Gilenya 1), whose active phosphate metabolite is an S1P1 full agonist, in terms of pulmonary and cardiovascular safety. S1P1 partial agonist 2, however, has a long half-life in rodents and was projected to have a long half-life in humans. The purpose of this communication is to disclose highly potent partial agonists of S1P1 with shorter half-lives relative to the clinical compound 2. PK/PD relationships as well as their preclinical pulmonary and cardiovascular safety assessment are discussed.

2.
ACS Med Chem Lett ; 6(8): 845-9, 2015 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-26288682

RESUMO

Early hit to lead work on a pyrrolopyridine chemotype provided access to compounds with biochemical and cellular potency against Janus kinase 2 (JAK2). Structure-based drug design along the extended hinge region of JAK2 led to the identification of an important H-bond interaction with the side chain of Tyr 931, which improved JAK family selectivity. The 4,5-dimethyl thiazole analogue 18 demonstrated high levels of JAK family selectivity and was identified as a promising lead for the program.

3.
ACS Med Chem Lett ; 6(8): 850-5, 2015 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-26288683

RESUMO

JAK2 kinase inhibitors are a promising new class of agents for the treatment of myeloproliferative neoplasms and have potential for the treatment of other diseases possessing a deregulated JAK2-STAT pathway. X-ray structure and ADME guided refinement of C-4 heterocycles to address metabolic liability present in dialkylthiazole 1 led to the discovery of a clinical candidate, BMS-911543 (11), with excellent kinome selectivity, in vivo PD activity, and safety profile.

4.
ACS Med Chem Lett ; 6(5): 523-7, 2015 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-26005526

RESUMO

Structure-activity relationships in a series of (2-oxo-1,4-benzodiazepin-3-yl)-succinamides identified highly potent inhibitors of γ-secretase mediated signaling of Notch1/2/3/4 receptors. On the basis of its robust in vivo efficacy at tolerated doses in Notch driven leukemia and solid tumor xenograft models, 12 (BMS-906024) was selected as a candidate for clinical evaluation.

5.
Bioorg Med Chem Lett ; 25(14): 2809-12, 2015 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-25987372
6.
J Med Chem ; 56(20): 7772-87, 2013 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-24083782

RESUMO

XIAP is a key regulator of apoptosis, and its overexpression in cancer cells may contribute to their survival. The antiapoptotic function of XIAP derives from its BIR domains, which bind to and inhibit pro-apoptotic caspases. Most known IAP inhibitors are selective for the BIR3 domain and bind to cIAP1 and cIAP2 as well as XIAP. Pathways activated upon cIAP binding contribute to the function of these compounds. Inhibitors selective for XIAP should exert pro-apoptotic effects through competition with the terminal caspases. This paper details our synthetic explorations of a novel XIAP BIR2-selective benzazepinone screening hit with a focus on increasing BIR2 potency and overcoming high in vivo clearance. These efforts led to the discovery of benzoxazepinone 40, a potent BIR2-selective inhibitor with good in vivo pharmacokinetic properties which potentiates apoptotic signaling in a manner mechanistically distinct from that of known pan-IAP inhibitors.


Assuntos
Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacologia , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/antagonistas & inibidores , Alanina/análogos & derivados , Alanina/síntese química , Alanina/farmacocinética , Alanina/farmacologia , Animais , Anticorpos Monoclonais/farmacologia , Apoptose/efeitos dos fármacos , Western Blotting , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Feminino , Compostos Heterocíclicos/farmacocinética , Humanos , Proteínas Inibidoras de Apoptose/química , Proteínas Inibidoras de Apoptose/metabolismo , Camundongos , Camundongos Nus , Modelos Químicos , Modelos Moleculares , Estrutura Molecular , Oxazepinas/síntese química , Oxazepinas/farmacocinética , Oxazepinas/farmacologia , Estrutura Terciária de Proteína , Ratos , Ubiquitina-Proteína Ligases , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/química , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
7.
J Med Chem ; 56(20): 7788-803, 2013 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-24093940

RESUMO

The IAPs are key regulators of the apoptotic pathways and are commonly overexpressed in many cancer cells. IAPs contain one to three BIR domains that are crucial for their inhibitory function. The pro-survival properties of XIAP come from binding of the BIR domains to the pro-apoptotic caspases. The BIR3 domain of XIAP binds and inhibits caspase 9, while the BIR2 domain binds and inhibits the terminal caspases 3 and 7. While XIAP BIR3 inhibitors have previously been reported, they also inhibit cIAP1/2 and promote the release of TNFα, potentially limiting their therapeutic utility. This paper will focus on the optimization of selective XIAP BIR2 inhibitors leading to the discovery of highly potent benzodiazepinone 36 (IC50 = 45 nM), which has high levels of selectivity over XIAP BIR3 and cIAP1 BIR2/3 and shows efficacy in a xenograft pharmacodynamic model monitoring caspase activity while not promoting the release of TNFα in vitro.


Assuntos
Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacologia , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/antagonistas & inibidores , Alanina/análogos & derivados , Alanina/síntese química , Alanina/farmacocinética , Alanina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Benzodiazepinonas/síntese química , Benzodiazepinonas/farmacocinética , Benzodiazepinonas/farmacologia , Western Blotting , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Feminino , Compostos Heterocíclicos/farmacocinética , Humanos , Proteínas Inibidoras de Apoptose/química , Proteínas Inibidoras de Apoptose/metabolismo , Camundongos , Camundongos Nus , Modelos Químicos , Modelos Moleculares , Estrutura Molecular , Estrutura Terciária de Proteína , Ubiquitina-Proteína Ligases , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/química , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Bioorg Med Chem Lett ; 22(12): 3951-6, 2012 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-22608393

RESUMO

5-Butyl-1,4-diphenyl pyrazole and 2-amino-5-chloro pyrimidine acylsulfonamides were developed as potent dual antagonists of Bcl-2 and Bcl-xL. Compounds were optimized for binding to the I88, L92, I95, and F99 pockets normally occupied by pro-apoptotic protein Bim. An X-ray crystal structure confirmed the proposed binding mode. Observation of cytochrome c release from isolated mitochondria in MV-411 cells provides further evidence of target inhibition. Compounds demonstrated submicromolar antiproliferative activity in Bcl-2/Bcl-xL dependent cell lines.


Assuntos
Antineoplásicos/síntese química , Pirazóis/síntese química , Pirimidinas/síntese química , Sulfonamidas/síntese química , Proteína X Associada a bcl-2/antagonistas & inibidores , Proteína bcl-X/antagonistas & inibidores , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/química , Proteínas Reguladoras de Apoptose/metabolismo , Proteína 11 Semelhante a Bcl-2 , Sítios de Ligação , Linhagem Celular Tumoral , Cristalografia por Raios X , Citocromos c/metabolismo , Humanos , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Modelos Moleculares , Ligação Proteica , Proteínas Proto-Oncogênicas/química , Proteínas Proto-Oncogênicas/metabolismo , Pirazóis/farmacologia , Pirimidinas/farmacologia , Sulfonamidas/farmacologia , Proteína X Associada a bcl-2/química , Proteína X Associada a bcl-2/metabolismo , Proteína bcl-X/química , Proteína bcl-X/metabolismo
9.
11.
Bioorg Med Chem Lett ; 20(9): 2998-3002, 2010 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-20382527

RESUMO

Biarylamine-based inhibitors of Met kinase have been identified. Lead compounds demonstrate nanomolar potency in Met kinase biochemical assays and significant activity in the Met-driven GTL-16 human gastric carcinoma cell line. X-ray crystallography revealed that these compounds adopt a bioactive conformation, in the kinase domain, consistent with that previously seen with 2-pyridone-based Met kinase inhibitors. Compound 9b demonstrated potent in vivo antitumor activity in the GTL-16 human tumor xenograft model.


Assuntos
Aminas/química , Aminopiridinas/síntese química , Antineoplásicos/síntese química , Inibidores de Proteínas Quinases/síntese química , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Aminopiridinas/química , Aminopiridinas/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Cristalografia por Raios X , Desenho de Drogas , Humanos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Mol Cancer Ther ; 9(2): 369-78, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20103604

RESUMO

Tumor angiogenesis is a complex and tightly regulated network mediated by various proangiogenic factors. The fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) family of growth factors, and associated tyrosine kinase receptors have a major influence in tumor growth and dissemination and may work synergistically to promote angiogenesis. Brivanib alaninate is the orally active prodrug of brivanib, a selective dual inhibitor of FGF and VEGF signaling. Here, we show that brivanib demonstrates antitumor activity in a broad range of xenograft models over multiple dose levels and that brivanib alaninate shows dose-dependent efficacy equivalent to brivanib in L2987 human tumor xenografts. Brivanib alaninate (107 mg/kg) reduced tumor cell proliferation as determined by a 76% reduction in Ki-67 staining and reduced tumor vascular density as determined by a 76% reduction in anti-CD34 endothelial cell staining. Furthermore, Matrigel plug assays in athymic mice showed that brivanib alaninate inhibited angiogenesis driven by VEGF or basic FGF alone, or combined. Dynamic contrast-enhanced magnetic resonance imaging, used to assess the effects of brivanib alaninate on tumor microcirculation, showed a marked decrease in gadopentetate dimeglumine contrast agent uptake at 107 mg/kg dose, with a reduction in area under the plasma concentration-time curve from time 0 to 60 minutes at 24 and 48 hours of 54% and 64%, respectively. These results show that brivanib alaninate is an effective antitumor agent in preclinical models across a range of doses, and that efficacy is accompanied by changes in cellular and vascular activities.


Assuntos
Pirróis/farmacologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Triazinas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Alanina/análogos & derivados , Animais , Antígenos CD34/biossíntese , Linhagem Celular Tumoral , Colágeno/química , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Feminino , Humanos , Laminina/química , Camundongos , Camundongos Endogâmicos BALB C , Transplante de Neoplasias , Proteoglicanas/química , Transdução de Sinais , Fatores de Tempo
13.
J Med Chem ; 52(5): 1251-4, 2009 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-19260711

RESUMO

Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.


Assuntos
Aminopiridinas/síntese química , Antineoplásicos/síntese química , Di-Hidropiridinas/síntese química , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Piridonas/síntese química , Administração Oral , Aminopiridinas/farmacocinética , Aminopiridinas/farmacologia , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Di-Hidropiridinas/farmacocinética , Di-Hidropiridinas/farmacologia , Cães , Humanos , Camundongos , Camundongos Nus , Modelos Moleculares , Piridonas/farmacocinética , Piridonas/farmacologia , Ratos , Solubilidade , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Drug Metab Dispos ; 36(12): 2475-83, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18787055

RESUMO

5-Isopropyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (BMS-645737) is a potent and selective vascular endothelial growth factor receptor-2 antagonist. In this study, liquid chromatography/tandem mass spectrometry and NMR were used to investigate the biotransformation of BMS-645737 in vitro and in the cynomolgus monkey, dog, mouse, and rat. Metabolic pathways for BMS-645737 included multistep processes involving both oxidation and conjugation reactions. For example, the 2-methyl-1H-pyrrolo moiety underwent cytochrome P450-catalyzed hydroxylation followed by oxidation to a carboxylic acid and then conjugation with taurine. Alternatively, the 5-methyl-1,3,4-oxadiazol-2-yl moiety was metabolized by hydroxylation and then conjugation with sulfate. The pyridin-5-yl group underwent direct glucuronidation in hepatocytes (dog, monkey, human) and conjugation with N-acetylglucosamine in the monkey. Conjugation with glutathione and processing along the mercapturic acid pathway was a minor metabolic pathway in vivo, although BMS-645737 did not form conjugates in the presence of glutathione-supplemented liver microsomes. Other minor biotransformation pathways included oxidative dehydrogenation, dihydroxylation, and hydrolytic opening of the oxadiazole ring followed by either deacetylation or hydrolysis of the resulting diacyl hydrazide. Whereas previous studies have shown the formation of N-acetylglucosamine conjugates of alcohols, arylamines, and other small molecules, this report describes the biotransformation of a heterocyclic aromatic amine via direct conjugation with N-acetylglucosamine.


Assuntos
Acetilglucosamina/metabolismo , Pirróis/metabolismo , Triazinas/metabolismo , Animais , Bile/metabolismo , Biotransformação , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Cães , Glicosilação , Hepatócitos/metabolismo , Humanos , Hidroxilação , Macaca fascicularis , Espectroscopia de Ressonância Magnética , Redes e Vias Metabólicas , Camundongos , Camundongos Endogâmicos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Pirróis/química , Pirróis/farmacocinética , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/metabolismo , Espectrometria de Massas em Tandem , Triazinas/química , Triazinas/farmacocinética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores
15.
J Med Chem ; 51(17): 5330-41, 2008 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-18690676

RESUMO

Conformationally constrained 2-pyridone analogue 2 is a potent Met kinase inhibitor with an IC50 value of 1.8 nM. Further SAR of the 2-pyridone based inhibitors of Met kinase led to potent 4-pyridone and pyridine N-oxide inhibitors such as 3 and 4. The X-ray crystallographic data of the inhibitor 2 bound to the ATP binding site of Met kinase protein provided insight into the binding modes of these inhibitors, and the SAR of this series of analogues was rationalized. Many of these analogues showed potent antiproliferative activities against the Met dependent GTL-16 gastric carcinoma cell line. Compound 2 also inhibited Flt-3 and VEGFR-2 kinases with IC50 values of 4 and 27 nM, respectively. It possesses a favorable pharmacokinetic profile in mice and demonstrates significant in vivo antitumor activity in the GTL-16 human gastric carcinoma xenograft model.


Assuntos
Antineoplásicos/síntese química , Fosfotransferases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Piridonas/farmacologia , Receptores de Fatores de Crescimento/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas c-met , Piridonas/síntese química , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores
16.
Bioorg Med Chem Lett ; 18(11): 3224-9, 2008 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-18479916

RESUMO

A series of acylurea analogs derived from pyrrolopyridine and aminopyridine scaffolds were identified as potent inhibitors of Met kinase activity. The SAR at various positions of the two kinase scaffolds was investigated. These studies led to the discovery of compounds 3b and 20b, which demonstrated favorable pharmacokinetic properties in mice and significant antitumor activity in a human gastric carcinoma xenograft model.


Assuntos
Aminopiridinas/síntese química , Aminopiridinas/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Pirróis/síntese química , Pirróis/farmacologia , Ureia/síntese química , Ureia/farmacologia , Aminopiridinas/química , Animais , Humanos , Camundongos , Inibidores de Proteínas Quinases/química , Pirróis/química , Neoplasias Gástricas/induzido quimicamente , Neoplasias Gástricas/patologia , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Bioorg Med Chem Lett ; 18(9): 2985-9, 2008 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-18395443

RESUMO

We report herein a series of substituted N-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amines as inhibitors of vascular endothelial growth factor receptor-2 tyrosine kinase. Through structure-activity relationship studies, biochemical potency, pharmacokinetics, and kinase selectivity were optimized to afford BMS-645737 (13), a compound with good preclinical in vivo activity against human tumor xenograft models.


Assuntos
Inibidores da Angiogênese/farmacologia , Desenho de Drogas , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirróis/farmacologia , Triazinas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/síntese química , Animais , Linhagem Celular , Inibidores do Citocromo P-450 CYP3A , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Endogâmicos BALB C , Pirróis/síntese química , Relação Estrutura-Atividade , Triazinas/síntese química , Ensaios Antitumorais Modelo de Xenoenxerto
18.
J Med Chem ; 51(6): 1976-80, 2008 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-18288793

RESUMO

A series of amino acid ester prodrugs of the dual VEGFR-2/FGFR-1 kinase inhibitor 1 (BMS-540215) was prepared in an effort to improve the aqueous solubility and oral bioavailability of the parent compound. These prodrugs were evaluated for their ability to liberate parent drug 1 in in vitro and in vivo systems. The l-alanine prodrug 8 (also known as brivanib alaninate/BMS-582664) was selected as a development candidate and is presently in phase II clinical trials.


Assuntos
Carcinoma/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Pró-Fármacos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirróis/farmacologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Triazinas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Administração Oral , Alanina/análogos & derivados , Animais , Disponibilidade Biológica , Proliferação de Células/efeitos dos fármacos , Ensaios Clínicos Fase II como Assunto , Desenho de Drogas , Avaliação Pré-Clínica de Medicamentos , Humanos , Intestinos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Camundongos , Microssomos/efeitos dos fármacos , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirróis/síntese química , Pirróis/química , Solubilidade , Estereoisomerismo , Triazinas/síntese química , Triazinas/química , Água/química , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Bioorg Med Chem Lett ; 18(6): 1945-51, 2008 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-18289854

RESUMO

An amide library derived from the pyrrolo[2,1-f][1,2,4]triazine scaffold led to the identification of modest inhibitors of Met kinase activity. Introduction of polar side chains at C-6 of the pyrrolotriazine core provided significant improvements in in vitro potency. The amide moiety could be replaced with acylurea and malonamide substituents to give compounds with improved potency in the Met-driven GTL-16 human gastric carcinoma cell line. Acylurea pyrrolotriazines with substitution at C-5 demonstrated single digit nanomolar kinase activity. X-ray crystallography revealed that the C-5 substituted pyrrolotriazines bind to the Met kinase domain in an ATP-competitive manner.


Assuntos
Inibidores Enzimáticos/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Pirróis/química , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores de Fatores de Crescimento/antagonistas & inibidores , Neoplasias Gástricas/tratamento farmacológico , Triazinas/química , Animais , Células CACO-2/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas/efeitos dos fármacos , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Glutationa Transferase/antagonistas & inibidores , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Conformação Proteica , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-met , Receptores Proteína Tirosina Quinases/metabolismo , Receptores de Fatores de Crescimento/metabolismo , Neoplasias Gástricas/sangue , Neoplasias Gástricas/enzimologia , Relação Estrutura-Atividade
20.
Bioorg Med Chem Lett ; 18(4): 1354-8, 2008 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-18221875

RESUMO

Introduction of the 2,4-difluoro-5-(cyclopropylcarbamoyl)phenylamino group at the C-4 position of the pyrrolo[2,1-f][1,2,4] triazine scaffold led to the discovery of a novel sub-series of inhibitors of VEGFR-2 kinase activity. Subsequent SAR studies on the 1,3,5-oxadiazole ring appended to the C-6 position of this new sub-family of pyrrolotriazines resulted in the identification of low nanomolar inhibitors of VEGFR-2. Antitumor efficacy was observed with compound 37 against L2987 human lung carcinoma xenografts in athymic mice.


Assuntos
Ciclopropanos/química , Ciclopropanos/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Triazinas/química , Triazinas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Ciclopropanos/síntese química , Inibidores das Enzimas do Citocromo P-450 , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Camundongos Nus , Oxidiazóis/síntese química , Oxidiazóis/química , Oxidiazóis/farmacologia , Inibidores de Proteínas Quinases/química , Pirróis/síntese química , Pirróis/química , Pirróis/farmacologia , Relação Estrutura-Atividade , Triazinas/síntese química , Ensaios Antitumorais Modelo de Xenoenxerto
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA