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2.
Eur J Med Chem ; 45(4): 1379-86, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20074837

RESUMO

A series of 8,9-dimethoxy-5-(2-aminoalkoxy-pyridin-3-yl)-benzo[c][2,7]naphthyridin-4-ylamine-based inhibitors of 3-phosphoinositide-dependent kinase-1 (PDK-1) has been identified. Several examples appear to be potent and relatively selective inhibitors of PDK-1 over the related AGC kinases PKA, PKB/AKT, and p70S6K. The introduction of a stereochemical center beside the amino substituent on the aminoalkoxy-side chain had little effect upon the inhibitory activity against these enzymes, and X-ray crystallographic analyses of a representative pair of enantiomeric inhibitors bound to the active site of PDK-1 revealed comparable binding modes for each enantiomer.


Assuntos
Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Piridinas/farmacologia , Proteínas Quinases Dependentes de 3-Fosfoinositídeo , Cristalografia por Raios X , Ligação de Hidrogênio , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Piridinas/química , Eletricidade Estática , Relação Estrutura-Atividade
4.
Bioorg Med Chem Lett ; 19(9): 2461-3, 2009 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-19345579

RESUMO

A series of 4-indolylamino-5-phenyl-3-pyridinecarbonitrile inhibitors of PKCtheta were synthesized as potential anti-inflammatory agents. The effects of specific substitution on the 5-phenyl moiety and variations of the positional isomers of the 4-indolylamino substituent were explored. This study led to the discovery of compound 12d, which had an IC(50) value of 18nM for the inhibition of PKCtheta.


Assuntos
Isoenzimas/antagonistas & inibidores , Proteína Quinase C/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Piridinas/síntese química , Trifosfato de Adenosina/química , Animais , Anti-Inflamatórios/farmacologia , Química Farmacêutica/métodos , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Isoenzimas/química , Camundongos , Modelos Químicos , Estrutura Molecular , Isoformas de Proteínas , Proteína Quinase C/química , Proteína Quinase C-theta , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Relação Estrutura-Atividade
6.
J Med Chem ; 51(19): 5958-63, 2008 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-18783200

RESUMO

The protein kinase C (PKC) family of serine/threonine kinases is implicated in a wide variety of cellular processes. The PKC theta (PKCtheta) isoform is involved in TCR signal transduction and T cell activation and regulates T cell mediated diseases, including lung inflammation and airway hyperresponsiveness. Thus inhibition of PKCtheta enzyme activity by a small molecule represents an attractive strategy for the treatment of asthma. A PKCtheta high-throughput screening (HTS) campaign led to the identification of 4-(3-bromophenylamino)-5-(3,4-dimethoxyphenyl)-3-pyridinecarbonitrile 4a, a low microM ATP competitive PKCtheta inhibitor. Structure based hit-to-lead optimization led to the identification of 5-(3,4-dimethoxyphenyl)-4-(1H-indol-5-ylamino)-3-pyridinecarbonitrile 4p, a 70 nM PKCtheta inhibitor. Compound 4p was selective for inhibition of novel PKC isoforms over a panel of 21 serine/threonine, tyrosine, and phosphoinositol kinases, in addition to the conventional and atypical PKCs, PKCbeta, and PKCzeta, respectively. Compound 4p also inhibited IL-2 production in antiCD3/anti-CD28 activated T cells enriched from splenocytes.


Assuntos
Indóis/farmacologia , Isoenzimas/antagonistas & inibidores , Nitrilas/farmacologia , Proteína Quinase C/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Animais , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Feminino , Indóis/síntese química , Indóis/química , Interleucina-2/antagonistas & inibidores , Interleucina-2/biossíntese , Isoenzimas/deficiência , Isoenzimas/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Moleculares , Estrutura Molecular , Nitrilas/síntese química , Nitrilas/química , Proteína Quinase C/deficiência , Proteína Quinase C/efeitos dos fármacos , Proteína Quinase C-theta , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Piridinas/síntese química , Piridinas/química , Baço/citologia , Baço/efeitos dos fármacos , Baço/imunologia , Estereoisomerismo , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
7.
Arch Pharm (Weinheim) ; 341(8): 465-77, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18493974

RESUMO

The development of HKI-272 and EKB-569 for the treatment of cancer is described. These compounds function as irreversible inhibitors of some members of the ErbB family of receptor tyrosine kinases. In particular, they target epidermal growth factor receptor (EGFR, also known as ErbB-1) and human epidermal growth factor receptor-2 (HER2, also known as ErbB-2). Both, HKI-272 and EKB-569 are 4-anilino-3-cyano quinoline derivatives that contain a 4-(dimethylamino)crotonamide Michael-acceptor group at the 6-position. These compounds inhibit the function of the target enzymes by forming a covalent interaction with a conserved cysteine residue located in the kinase domains of these proteins. The potential advantages of using irreversible inhibitors for this purpose are discussed. We summarize the recent findings concerning some somatic mutations in EGFR and their relevance with respect to the irreversible inhibitors. In particular, we highlight the findings that these irreversible inhibitors retain activity against tumors that have acquired a resistance to the reversible binding inhibitors gefitinib and erlotinib. The promising interim clinical trial results for HKI-272 and EKB-569 in treating colon, lung, and breast cancers are summarized.


Assuntos
Aminoquinolinas/uso terapêutico , Compostos de Anilina/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Quinolinas/uso terapêutico , Aminoquinolinas/síntese química , Compostos de Anilina/síntese química , Antineoplásicos/síntese química , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Quinolinas/síntese química , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/metabolismo
8.
Bioorg Med Chem ; 15(11): 3635-48, 2007 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-17416531

RESUMO

A series of 4-dimethylamino-but-2-enoic acid [4-(3,6-dioxo-cyclohexa-1,4-dienylamino)-7-ethoxy-quinazolin-6-yl]-amide derivatives were prepared. These compounds have two independent reactive centers and were designed to function as dual irreversible inhibitors of the kinase domains of both Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) where each reactive center targets a different, non-conserved, cysteine residue located in the ATP binding pocket of these enzymes. The compounds contain a 6-(4-(dimethylamino) crotonamide) Michael acceptor group that targets Cys-773 in EGFR and a 4-(amino-[1,4]benzoquinone) moiety that targets Cys-1045 in VEGFR-2. In vitro studies indicated that most of these compounds are relatively potent inhibitors of each enzyme. These inhibitors were compared with reference compounds that lack one or both of the reactive centers. The relative dependence of the IC(50) values on the concentration of ATP used in the assays suggests that these compounds appear to function as irreversible inhibitors of each kinase.


Assuntos
Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/química , Quinazolinas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Trifosfato de Adenosina/química , Trifosfato de Adenosina/metabolismo , Sítios de Ligação , Bioensaio , Células Cultivadas , Receptores ErbB/química , Receptores ErbB/metabolismo , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Conformação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/síntese química , Quinazolinas/síntese química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
9.
J Med Chem ; 48(24): 7560-81, 2005 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-16302797

RESUMO

A series of 2-(quinazolin-4-ylamino)-[1,4] benzoquinone derivatives that function as potent covalent-binding, irreversible inhibitors of the kinase domain of vascular endothelial growth factor receptor-2 (VEGFR-2) has been prepared by ceric ammonium nitrate oxidation of substituted (2,5-dimethoxyphenyl)(6,7-disubstituted-quinazolin-4-yl)amines and by displacement of the chlorine atom of substituted 2-chloro-5-(6,7-disubstituted-quinazolin-4-ylamino)-[1,4]benzoquinones with various amines, anilines, phenols, and alcohols. Enzyme studies were conducted in the absence and presence of glutathione and plasma. Several of the compounds inhibit VEGF-stimulated autophosphorylation in intact cells. Kinetic experiments were performed to study the reactivity of selected inhibitors toward glutathione. Reactivities correlated with LUMO energies calculated as averages of those of individual conformers weighted by the Boltzmann distribution. These results and molecular modeling were used to rationalize the biological observations. The compounds behave as non-ATP-competitive inhibitors. Unequivocal evidence, from mass spectral studies, indicates that these inhibitors form a covalent interaction with Cys-1045. One member of this series displays antitumor activity in an in vivo model.


Assuntos
Inibidores da Angiogênese/síntese química , Benzoquinonas/síntese química , Quinazolinas/síntese química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Trifosfato de Adenosina/metabolismo , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Animais , Benzoquinonas/química , Benzoquinonas/farmacologia , Sítios de Ligação , Linhagem Celular , Feminino , Glutationa/química , Humanos , Cinética , Camundongos , Camundongos Nus , Modelos Moleculares , Conformação Molecular , Fosforilação , Ligação Proteica , Estrutura Terciária de Proteína , Teoria Quântica , Quinazolinas/química , Quinazolinas/farmacologia , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Proc Natl Acad Sci U S A ; 102(21): 7665-70, 2005 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-15897464

RESUMO

Non-small cell lung cancers (NSCLCs) with activating mutations in the kinase domain of the epidermal growth factor receptor (EGFR) demonstrate dramatic, but transient, responses to the reversible tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva). Some recurrent tumors have a common secondary mutation in the EGFR kinase domain, T790M, conferring drug resistance, but in other cases the mechanism underlying acquired resistance is unknown. In studying multiple sites of recurrent NSCLCs, we detected T790M in only a small percentage of tumor cells. To identify additional mechanisms of acquired resistance to gefitinib, we used NSCLC cells harboring an activating EGFR mutation to generate multiple resistant clones in vitro. These drug-resistant cells demonstrate continued dependence on EGFR and ERBB2 signaling for their viability and have not acquired secondary EGFR mutations. However, they display increased internalization of ligand-activated EGFR, consistent with altered receptor trafficking. Although gefitinib-resistant clones are cross-resistant to related anilinoquinazolines, they demonstrate sensitivity to a class of irreversible inhibitors of EGFR. These inhibitors also show effective inhibition of signaling by T790M-mutant EGFR and killing of NSCLC cells with the T790M mutation. Both mechanisms of gefitinib resistance are therefore circumvented by irreversible tyrosine kinase inhibitors. Our findings suggest that one of these, HKI-272, may prove highly effective in the treatment of EGFR-mutant NSCLCs, including tumors that have become resistant to gefitinib or erlotinib.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Resistência a Medicamentos/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Recidiva Local de Neoplasia/genética , Quinazolinas/metabolismo , Aminoquinolinas , Compostos de Anilina , Sequência de Bases , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/fisiologia , Cloridrato de Erlotinib , Gefitinibe , Humanos , Immunoblotting , Neoplasias Pulmonares/metabolismo , Dados de Sequência Molecular , Mutação/genética , Recidiva Local de Neoplasia/metabolismo , Compostos Orgânicos/farmacologia , Fosforilação/efeitos dos fármacos , Quinolinas/farmacologia , Receptor ErbB-2/fisiologia , Análise de Sequência de DNA , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Células Tumorais Cultivadas
11.
J Med Chem ; 48(4): 1107-31, 2005 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-15715478

RESUMO

A series of new 6,7-disubstituted-4-(arylamino)quinoline-3-carbonitrile derivatives that function as irreversible inhibitors of human epidermal growth factor receptor-2 (HER-2) and epidermal growth factor receptor (EGFR) kinases have been prepared. These compounds demonstrated enhanced activities for inhibiting HER-2 kinase and the growth of HER-2 positive cells compared to our EGFR kinase inhibitor 86 (EKB-569). Three synthetic routes were used to prepare these compounds. They were prepared mostly by acylation of 6-amino-4-(arylamino)quinoline-3-carbonitriles with unsaturated acid chlorides or by amination of 4-chloro-6-(crotonamido)quinoline-3-carbonitriles with monocyclic or bicyclic anilines. The third route was developed to prepare a key intermediate, 6-acetamido-4-chloroquinoline-3-carbonitrile, that involved a safer cyclization step. We show that attaching a large lipophilic group at the para position of the 4-(arylamino) ring results in improved potency for inhibiting HER-2 kinase. We also show the importance of a basic dialkylamino group at the end of the Michael acceptor for activity, due to intramolecular catalysis of the Michael addition. This, along with improved water solubility, resulted in compounds with enhanced biological properties. We present molecular modeling results consistent with the proposed mechanism of inhibition. Binding studies of one compound, 25o (C-14 radiolabeled), showed that it binds irreversibly to HER-2 protein in BT474 cells. Furthermore, it demonstrated excellent oral activity, especially in HER-2 overexpressing xenografts. Compound 25o (HKI-272) was selected for further studies and is currently in phase I clinical trials for the treatment of cancer.


Assuntos
Antineoplásicos/síntese química , Nitrilas/síntese química , Quinolinas/síntese química , Receptor ErbB-2/antagonistas & inibidores , Administração Oral , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Feminino , Humanos , Camundongos , Camundongos Nus , Modelos Moleculares , Nitrilas/química , Nitrilas/farmacologia , Fosforilação , Ligação Proteica , Quinolinas/química , Quinolinas/farmacologia , Ensaio Radioligante , Receptor ErbB-2/metabolismo , Relação Estrutura-Atividade , Transplante Heterólogo
12.
Cancer Res ; 64(11): 3958-65, 2004 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-15173008

RESUMO

HER-2 belongs to the ErbB family of receptor tyrosine kinases, which has been implicated in a variety of cancers. Overexpression of HER-2 is seen in 25-30% of breast cancer patients and predicts a poor outcome in patients with primary disease. Trastuzumab (Herceptin), a monoclonal antibody to HER-2, is specifically approved for HER-2-positive breast cancer but is active only in a subset of these tumors. Blocking HER-2 function by a small molecule kinase inhibitor, therefore, represents an attractive alternate strategy to inhibit the growth of HER-2-positive tumors. HKI-272 is a potent inhibitor of HER-2 and is highly active against HER-2-overexpressing human breast cancer cell lines in vitro. It also inhibits the epidermal growth factor receptor (EGFR) kinase and the proliferation of EGFR-dependent cells. HKI-272 reduces HER-2 receptor autophosphorylation in cells at doses consistent with inhibition of cell proliferation and functions as an irreversible binding inhibitor, most likely by targeting a cysteine residue in the ATP-binding pocket of the receptor. In agreement with the predicted effects of HER-2 inactivation, HKI-272 treatment of cells results in inhibition of downstream signal transduction events and cell cycle regulatory pathways. This leads to arrest at the G(1)-S (Gap 1/DNA synthesis)-phase transition of the cell division cycle, ultimately resulting in decreased cell proliferation. In vivo, HKI-272 is active in HER-2- and EGFR-dependent tumor xenograft models when dosed orally on a once daily schedule. On the basis of its favorable preclinical pharmacological profile, HKI-272 has been selected as a candidate for additional development as an antitumor agent in breast and other HER-2-dependent cancers.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Quinolinas/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Administração Oral , Animais , Ciclo Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Receptores ErbB/metabolismo , Feminino , Humanos , Sistema de Sinalização das MAP Quinases/fisiologia , Camundongos , Camundongos Nus , Fosforilação , Receptor ErbB-2/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Bioorg Med Chem Lett ; 14(6): 1411-6, 2004 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-15006373

RESUMO

The syntheses and EGFR kinase inhibitory activity of a series of 6-substituted-4-anilino [1,7] and [1,8] naphthyridine-3-carbonitriles are described. Both reversible and irreversible binding inhibitors were prepared. These series were compared with each other and with the corresponding 4-anilinoquinoline-3-carbonitriles. Compounds having a 1,7-naphthyridine core structure can retain high potency while those with a 1,8-naphthyridine core are significantly less active. These results are consistent with molecular modeling observations.


Assuntos
Inibidores Enzimáticos/síntese química , Receptores ErbB/antagonistas & inibidores , Naftiridinas/síntese química , Nitrilas/síntese química , Linhagem Celular Tumoral , Inibidores Enzimáticos/metabolismo , Receptores ErbB/metabolismo , Humanos , Naftiridinas/metabolismo , Nitrilas/metabolismo , Ligação Proteica/fisiologia
14.
Bioorg Med Chem Lett ; 13(18): 3031-4, 2003 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-12941327

RESUMO

4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)]anilino-6,7-diethoxy-3-quinolinecarbonitrile (3) was identified as a MEK1 kinase inhibitor with exceptional activity against LoVo cells. The structure-activity relationships of the C-4 aniline substituents were explored, and water-solubilizing groups were added at the C-7 position to improve physical properties. Secondary cellular assays revealed that a compound possessing the appropriate aniline substituents inhibited MEK1 as well as MAPK phosphorylation, thereby acting as a dual inhibitor of the Ras-MAPK signaling cascade.


Assuntos
Antineoplásicos/síntese química , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Nitrilas/síntese química , Animais , Antineoplásicos/farmacologia , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , MAP Quinase Quinase 1 , Camundongos , Neoplasias Experimentais/tratamento farmacológico , Nitrilas/farmacologia , Quinolinas/síntese química , Quinolinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Transplante Heterólogo , Resultado do Tratamento
15.
J Med Chem ; 46(1): 49-63, 2003 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-12502359

RESUMO

A series of of 6,7-disubstituted-4-anilinoquinoline-3-carbonitrile derivatives that function as irreversible inhibitors of EGFR and HER-2 kinases have been prepared. These inhibitors have, at the 6-position, butynamide, crotonamide, and methacrylamide Michael acceptors bearing water-solublilizing substituents. These compounds were prepared by acylation of 6-amino-4-(arylamino)quinoline-3-carbonitriles with unsaturated acid chlorides or mixed anhydrides. We performed competitive reactivity studies showing that attaching a dialkylamino group onto the end of the Michael acceptor results in compounds with greater reactivity due to intramolecular catalysis of the Michael addition. This, along with improved water-solubility results in compounds with enhanced biological properties. We present molecular modeling results consistent with the proposed mechanism of inhibition. One compound, 5 (EKB-569), which shows excellent oral in vivo activity, was selected for further studies and is currently in phase I clinical trials for the treatment of cancer.


Assuntos
Antineoplásicos/síntese química , Inibidores Enzimáticos/síntese química , Receptores ErbB/antagonistas & inibidores , Compostos Orgânicos , Receptor ErbB-2/antagonistas & inibidores , Administração Oral , Aminoquinolinas , Compostos de Anilina , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Divisão Celular/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Receptores ErbB/metabolismo , Glutationa/antagonistas & inibidores , Humanos , Camundongos , Modelos Moleculares , Fosforilação , Receptor ErbB-2/metabolismo , Relação Estrutura-Atividade , Especificidade por Substrato , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Bioorg Med Chem Lett ; 12(19): 2761-5, 2002 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-12217371

RESUMO

A series of 8-anilinoimidazo[4,5-g]quinoline-7-carbonitriles was synthesized and evaluated as Src kinase inhibitors. Several aniline substituents were surveyed, as well as water-solubilizing groups at the C-2 and N-3 positions. Potent Src inhibitors were identified, with N-3 providing the best position for an additional water-solubilizing group.


Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Nitrilas/síntese química , Nitrilas/farmacologia , Quinolinas/síntese química , Quinolinas/farmacologia , Quinases da Família src/antagonistas & inibidores , Fenômenos Químicos , Físico-Química , Indicadores e Reagentes , Solubilidade , Relação Estrutura-Atividade
17.
Bioorg Med Chem Lett ; 12(20): 2893-7, 2002 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-12270171

RESUMO

The syntheses and biological evaluations of 4-anilinoquinoline-3-carbonitrile analogues of the three clinical lead 4-anilinoquinazolines Iressa, Tarceva, and CI-1033 are described. The EGFR and HER-2 kinase inhibitory activities and the cell growth inhibition of the two series are compared with each other and with the clinical lead EKB-569. Similar activities are observed between these two series.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Receptores ErbB/antagonistas & inibidores , Nitrilas/síntese química , Nitrilas/farmacologia , Quinolinas/síntese química , Quinolinas/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Linhagem Celular , Ciclização , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Modelos Moleculares , Conformação Molecular
18.
Bioorg Med Chem Lett ; 12(20): 2989-92, 2002 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-12270190

RESUMO

A series of substituted 4-anilino-7-phenyl-3-quinolinecarbonitriles has been prepared as Src kinase inhibitors. Optimal activity is observed with compounds that have basic amines attached via the para position of the 7-phenyl ring, and a hydrogen atom at the C-6 position. The best compounds are low nanomolar inhibitors of Src kinase, and have potent activity against Src-transformed fibroblast cells.


Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Nitrilas/síntese química , Nitrilas/farmacologia , Quinolinas/síntese química , Quinolinas/farmacologia , Quinases da Família src/antagonistas & inibidores , Indicadores e Reagentes , Relação Estrutura-Atividade
19.
Bioorg Med Chem Lett ; 12(3): 423-5, 2002 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-11814812

RESUMO

A series of 4-anilino-3-cyanobenzo[g]quinolines was prepared as potent kinase inhibitors. Compared with their bicyclic 4-anilino-3-cyanoquinoline analogues, the tricyclic 4-anilino-3-cyanobenzo[g]quinolines are less active against EGF-R kinase, equally active against MAPK kinase (MEK), and more active against Src kinase. For Src kinase inhibition, the best activity is obtained when both the 7- and 8-positions are substituted with alkoxy groups. Several of these kinase inhibitors show potent growth inhibitory activity in tumor cells.


Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Nitrilas/síntese química , Nitrilas/farmacologia , Inibidores de Proteínas Quinases , Quinolinas/síntese química , Quinolinas/farmacologia , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Receptores ErbB/antagonistas & inibidores , Indicadores e Reagentes , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Relação Estrutura-Atividade , Especificidade por Substrato , Quinases da Família src/antagonistas & inibidores
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