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1.
Bioorg Med Chem Lett ; 22(18): 5995-8, 2012 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-22902653

RESUMO

A series of aminothiazoles that are potent inhibitors of LIM kinases 1 and 2 is described. Appropriate choice of substituents led to molecules with good selectivity for either enzyme. An advanced member of the series was shown to effectively interfere with the phosphorylation of the LIM kinases substrate cofilin. Consistent with the important role of the LIM kinases in regulating cytoskeletal structure, treated cells displayed dramatically reduced F-actin content.


Assuntos
Fatores de Despolimerização de Actina/metabolismo , Quinases Lim/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Tiazóis/farmacologia , Linhagem Celular , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Quinases Lim/metabolismo , Modelos Moleculares , Estrutura Molecular , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química
2.
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 Fármacos , 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
3.
Anal Biochem ; 392(1): 59-69, 2009 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-19497292

RESUMO

Eg5 is a kinesin whose inhibition leads to cycle arrest during mitosis, making it a potential therapeutic target in cancers. Circular dichroism and isothermal titration calorimetry of our pyrrolotriazine-4-one series of inhibitors with Eg5 motor domain revealed enhanced binding in the presence of adenosine 5'-diphosphate (ADP). Using this information, we studied the interaction of this series with ADP-Eg5 complexes using a thermal shift assay. We measured up to a 7 degrees C increase in the thermal melting (T(m)) of Eg5 for an inhibitor that produced IC(50) values of 60 and 130 nM in microtubule-dependent adenosine triphosphatase (ATPase) and cell-based cytotoxicity assays, respectively. In general, the inhibitor potency of the pyrrolotriazine-4-one series in in vitro biological assays correlated with the magnitude of the thermal stability enhancement of ADP-Eg5. The thermal shift assay also confirmed direct binding of Eg5 inhibitors identified in a high-throughput screen and demonstrated that the thermal shift assay is applicable to a range of chemotypes and can be useful in evaluating both potent (nM) and relatively weakly binding (microM) leads. Overall, the thermal shift assay was found to be an excellent biophysical method for evaluating direct binding of a large number of compounds to Eg5, and it complemented the catalytic assay screens by providing an alternative determination of inhibitor potency.


Assuntos
Bioquímica/métodos , Cinesina/química , Pirróis/análise , Pirróis/química , Triazinas/análise , Triazinas/química , Difosfato de Adenosina/metabolismo , Fenômenos Biofísicos , Calorimetria , Linhagem Celular Tumoral , Dicroísmo Circular , Humanos , Cinesina/metabolismo , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Ligação Proteica , Desnaturação Proteica , Dobramento de Proteína , Estrutura Terciária de Proteína , Temperatura
4.
Bioorg Med Chem Lett ; 18(6): 1869-73, 2008 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-18313297

RESUMO

SAR studies were conducted around lead compound 1 using high-throughput parallel solution and solid phase synthesis. Our lead optimization efforts led to the identification of several CCR2b antagonists with potent activity in both binding and functional assays [Compound 71 CCR2b Binding IC(50) 3.2 nM; MCP-1-Induced Chemotaxis IC(50) 0.83 nM; Ca(2+) Flux IC(50) 7.5 nM].


Assuntos
Quimiocina CCL2/metabolismo , Quimiotaxia/efeitos dos fármacos , Pirrolidinas/farmacologia , Receptores CCR2/antagonistas & inibidores , Cálcio/metabolismo , Células Cultivadas , Cromatografia Líquida de Alta Pressão , Fluorescência , Humanos , Rim/citologia , Rim/efeitos dos fármacos , Rim/metabolismo , Estrutura Molecular , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Pirrolidinas/síntese química , Receptores CCR2/metabolismo , Relação Estrutura-Atividade , Transfecção
5.
Org Lett ; 9(9): 1711-4, 2007 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-17385875

RESUMO

[reaction: see text] New methods for the palladium-catalyzed cyanation of aryl and heteroaryl chlorides have been developed, featuring sterically demanding, electron-rich phosphines. Highly challenging electron-rich aryl chlorides, in addition to electron-neutral and electron-deficient substrates, as well as nitrogen- and sulfur-containing heteroaryl chlorides can all undergo efficient cyanation under relatively mild conditions using readily available materials. In terms of substrate scope and temperature, these methods compare very favorably with the state-of-the-art cyanations of aryl chlorides.


Assuntos
Cloretos/química , Cianetos/química , Paládio/química , Compostos de Anilina/química , Catálise , Cloretos/síntese química , Ligantes , Estrutura Molecular
7.
Bioorg Med Chem Lett ; 14(21): 5407-11, 2004 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-15454235

RESUMO

N,N'-Disubstituted homopiperazine derivatives have been discovered as CC-chemokine receptor 2b (CCR2b) inhibitors with submicromolar activity in the CCR2b binding assay. A 4-substituted benzyl group on one homopiperazine nitrogen was an important moiety for binding affinity to the CCR2b receptor. The SAR for CCR2b binding affinity correlated inversely with the sigma factor of the functional group on this benzyl moiety. Introduction of hydroxy groups to appropriate positions in the 3,3-diphenylpropyl group on the other homopiperazine nitrogen increased CCR2b binding activity. The synthesis of an informer library to search for alternative substructures is also described.


Assuntos
Piperazinas/síntese química , Receptores de Quimiocinas/antagonistas & inibidores , Linhagem Celular , Quimiocina CCL2/metabolismo , Técnicas de Química Combinatória , Desenho de Fármacos , Humanos , Piperazinas/química , Piperazinas/farmacologia , Ensaio Radioligante , Receptores CCR2 , Relação Estrutura-Atividade
9.
Curr Top Med Chem ; 4(10): 1045-57, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15193138

RESUMO

Since their discovery, non-nucleoside reverse transcriptase inhibitors (NNRTIs) have become one of the cornerstones of highly active anti-retroviral therapy (HAART). Currently, three NNRTI agents, efavirenz, nevirapine and delavirdine are commercially available. Efavirenz and nevirapine, used in combination with nucleoside reverse transcriptase inhibitors (NRTIs), provide durable regimens with efficacy comparable to protease inhibitor (PI) containing therapies. When virological failure occurs following treatment with an NNRTI, the resistance mutations can confer reduced sensitivity to the entire agent class. Therefore, the strategy for the development of next generation NNRTIs has been to focus on compounds which have improved potencies against the clinically relevant viral mutants. Agents with improved virological profiles and which maintain the ease of administration and favorable safety profiles of the current agents should find use in anti-retroviral naïve patients as well as in components of salvage regimens in the anti-retroviral experienced patient. This review summarizes the recent developments with compounds in clinical trials as of January 2002 as well as to summarize information on new agents appearing in the primary and patent literature between January 2001 and December 2002.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Transcriptase Reversa do HIV/antagonistas & inibidores , Inibidores da Transcriptase Reversa/uso terapêutico , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Ensaios Clínicos como Assunto , Cumarínicos/farmacologia , Cumarínicos/uso terapêutico , Humanos , Imidazóis , Estrutura Molecular , Patentes como Assunto , Piranocumarinas , Piridazinas/farmacologia , Piridazinas/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Compostos de Enxofre
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