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1.
J Med Chem ; 59(19): 9173-9200, 2016 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-27583770

RESUMO

Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a member of the Tec family of kinases. BTK plays an essential role in B cell receptor (BCR)-mediated signaling as well as Fcγ receptor signaling in monocytes and Fcε receptor signaling in mast cells and basophils, all of which have been implicated in the pathophysiology of autoimmune disease. As a result, inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as lupus and rheumatoid arthritis. This article details the structure-activity relationships (SAR) leading to a novel series of highly potent and selective carbazole and tetrahydrocarbazole based, reversible inhibitors of BTK. Of particular interest is that two atropisomeric centers were rotationally locked to provide a single, stable atropisomer, resulting in enhanced potency and selectivity as well as a reduction in safety liabilities. With significantly enhanced potency and selectivity, excellent in vivo properties and efficacy, and a very desirable tolerability and safety profile, 14f (BMS-986142) was advanced into clinical studies.


Assuntos
Carbazóis/química , Carbazóis/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia , Animais , Carbazóis/farmacocinética , Cristalografia por Raios X , Feminino , Humanos , Isomerismo , Macaca fascicularis , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Tirosina Quinases/metabolismo , Quinazolinas/química , Quinazolinas/farmacocinética , Quinazolinas/farmacologia , Relação Estrutura-Atividade
2.
J Med Chem ; 59(17): 7915-35, 2016 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-27531604

RESUMO

Bruton's tyrosine kinase (BTK) belongs to the TEC family of nonreceptor tyrosine kinases and plays a critical role in multiple cell types responsible for numerous autoimmune diseases. This article will detail the structure-activity relationships (SARs) leading to a novel second generation series of potent and selective reversible carbazole inhibitors of BTK. With an excellent pharmacokinetic profile as well as demonstrated in vivo activity and an acceptable safety profile, 7-(2-hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9H-carbazole-1-carboxamide 6 (BMS-935177) was selected to advance into clinical development.


Assuntos
Antirreumáticos/química , Carbazóis/química , Proteínas Tirosina Quinases/antagonistas & inibidores , Quinazolinonas/química , Administração Oral , Tirosina Quinase da Agamaglobulinemia , Animais , Antirreumáticos/síntese química , Antirreumáticos/farmacocinética , Antirreumáticos/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Disponibilidade Biológica , Carbazóis/síntese química , Carbazóis/farmacocinética , Carbazóis/farmacologia , Linhagem Celular , Cristalografia por Raios X , Cães , Humanos , Macaca fascicularis , Camundongos , Microssomos Hepáticos/metabolismo , Permeabilidade , Proteínas Tirosina Quinases/química , Quinazolinonas/síntese química , Quinazolinonas/farmacocinética , Quinazolinonas/farmacologia , Relação Estrutura-Atividade
3.
Bioorg Med Chem Lett ; 24(9): 2206-11, 2014 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-24685542

RESUMO

Investigation of various heterocyclic core isosteres of imidazopyrazines 1 & 2 yielded purine derivatives 3 & 8 as potent and selective BTK inhibitors. Subsequent SAR studies of the purine series led to the discovery of 20 as a leading compound. Compound 20 is very selective when screened against a panel of 400 kinases and is a potent inhibitor in cellular assays of human B cell function including B-Cell proliferation and CD86 cell surface expression and exhibited in vivo efficacy in a mouse PCA model. Its X-ray co-crystal structure with BTK shows that the high selectivity is gained from filling a BTK specific lipophilic pocket. However, physical and ADME properties leading to low oral exposure hindered further development.


Assuntos
Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Purinas/química , Purinas/farmacologia , Tirosina Quinase da Agamaglobulinemia , Animais , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/enzimologia , Linfócitos B/efeitos dos fármacos , Cristalografia por Raios X , Humanos , Camundongos , Modelos Moleculares , Anafilaxia Cutânea Passiva/efeitos dos fármacos , Proteínas Tirosina Quinases/metabolismo , Ratos
4.
Bioorg Med Chem Lett ; 22(3): 1384-7, 2012 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-22225639

RESUMO

We report the synthesis of 3-phenylsulfonylmethyl cyclohexylaminobenzamides (4) as CCR2 inhibitors for the potential treatment of inflammatory diseases. Several of the compounds display nanomolar binding affinity for CCR2. The in vitro structure-activity relationships of 4 are described, and are also reconciled with those from the related 2-phenylsulfonylmethyl series.


Assuntos
Amidas/síntese química , Aminobenzoatos/síntese química , Modelos Moleculares , Receptores CCR2/antagonistas & inibidores , Enxofre/química , Amidas/química , Amidas/farmacologia , Aminobenzoatos/química , Aminobenzoatos/farmacologia , Animais , Ciclização , Humanos , Concentração Inibidora 50 , Camundongos , Microssomos/enzimologia , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Especificidade por Substrato , Enxofre/farmacologia
5.
Bioorg Med Chem Lett ; 18(2): 576-85, 2008 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-18096386

RESUMO

Conformational analysis of trans-1,2-disubstituted cyclohexane CCR3 antagonist 2 revealed that the cyclohexane linker could be replaced by an acyclic syn-alpha-methyl-beta-hydroxypropyl linker. Synthesis and biological evaluation of mono- and disubstituted propyl linkers support this conformational correlation. It was also found that the alpha-methyl group to the urea lowered protein binding and that the beta-hydroxyl group lowered affinity for CYP2D6. Ab initio calculations show that the alpha-methyl group governs the spatial orientation of three key functionalities within the molecule. alpha-Methyl-beta-hydroxypropyl urea 31 with a chemotaxis IC(50)=38 pM for eosinophils was chosen to enter clinical development for the treatment of asthma.


Assuntos
Quimiotaxia de Leucócito/efeitos dos fármacos , Eosinófilos/efeitos dos fármacos , Piperidinas/farmacologia , Receptores CCR3/antagonistas & inibidores , Ureia/análogos & derivados , Administração Oral , Animais , Inibidores das Enzimas do Citocromo P-450 , Cães , Eosinófilos/citologia , Ligações de Hidrogênio , Camundongos , Conformação Molecular , Piperidinas/química , Piperidinas/farmacocinética , Ratos , Relação Estrutura-Atividade , Ureia/química , Ureia/farmacocinética , Ureia/farmacologia
6.
Curr Opin Drug Discov Devel ; 9(4): 516-24, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16889234

RESUMO

Selective eosinophil recruitment into inflammatory sites and their subsequent activation is a characteristic of allergic diseases, such as asthma, rhinitis and atopic dermatitis. CC chemokine receptor-3 (CCR3) is the principal mediator of eosinophil chemotaxis and is expressed on a variety of inflammatory cells associated with allergic responses; these cells include basophils, mast cells and T-helper-2 lymphocytes, and resident tissue cells such as airway epithelium. Animal studies suggest that CCR3 is a prominent mediator of allergic responses and that antagonizing the receptor will lead to a reduction in airway inflammation. The potential importance of CCR3 in allergic inflammation has made this receptor a target for drug development. This review summarizes the efforts in this research area that have been reported in the last two years.


Assuntos
Receptores de Quimiocinas/antagonistas & inibidores , Tecnologia Farmacêutica/tendências , Animais , Quimiocinas CC/química , Quimiocinas CC/farmacologia , Humanos , Receptores CCR3 , Receptores de Quimiocinas/metabolismo , Tecnologia Farmacêutica/métodos
7.
J Med Chem ; 48(6): 2194-211, 2005 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-15771462

RESUMO

Starting with our previously described(20) class of CC chemokine receptor-3 (CCR3) antagonist, we improved the potency by replacing the phenyl linker of 1 with a cyclohexyl linker and by replacing the 4-benzylpiperidine with a 3-benzylpiperidine. The resulting compound, 32, is a potent and selective antagonist of CCR3. SAR studies showed that the 3-acetylphenyl urea of 32 could be replaced with heterocyclic ureas or heterocyclic-substituted phenyl ureas and still maintain the potency (inhibition of eotaxin-induced chemotaxis) of this class of compounds in the low-picomolar range (IC(50) = 10-60 pM), representing some of the most potent CCR3 antagonists reported to date. The potency of 32 for mouse CCR3 (chemotaxis IC(50) = 41 nM) and its oral bioavailability in mice (20% F ) were adequate to assess the efficacy in animal models of allergic airway inflammation. Oral administration of 32 reduced eosinophil recruitment into the lungs in a dose-dependent manner in these animal models. On the basis of its overall potency, selectivity, efficacy, and safety profile, the benzenesulfonate salt of 32, designated DPC168, entered phase I clinical trials.


Assuntos
Cicloexanos/síntese química , Compostos de Fenilureia/síntese química , Piperidinas/síntese química , Receptores de Quimiocinas/antagonistas & inibidores , Animais , Disponibilidade Biológica , Células CHO , Células CACO-2 , Cálcio/metabolismo , Quimiotaxia de Leucócito/efeitos dos fármacos , Cricetinae , Cicloexanos/química , Cicloexanos/farmacologia , Eosinófilos/efeitos dos fármacos , Eosinófilos/fisiologia , Feminino , Humanos , Hipersensibilidade/tratamento farmacológico , Hipersensibilidade/imunologia , Técnicas In Vitro , Inflamação/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Permeabilidade , Compostos de Fenilureia/química , Compostos de Fenilureia/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Receptores CCR3 , Estereoisomerismo , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/síntese química , Ureia/química , Ureia/farmacologia
8.
J Med Chem ; 45(17): 3794-804, 2002 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-12166951

RESUMO

Structure-activity relationship (SAR) studies of initial screening hits from our corporate library of compounds and a structurally related series of CCR1 receptor antagonists were used to determine that an N-(alkyl)benzylpiperidine is an essential pharmacophore for selective CCR3 antagonists. Further SAR studies that introduced N-(ureidoalkyl) substituents improved the binding potency of these compounds from the micromolar to the low nanomolar range. This new series of compounds also displays highly potent, in vitro functional CCR3-mediated antagonism of eotaxin-induced Ca(2+) mobilization and chemotaxis of human eosinophils.


Assuntos
Antialérgicos/síntese química , Piperidinas/síntese química , Receptores de Quimiocinas/antagonistas & inibidores , Ureia/análogos & derivados , Ureia/síntese química , Animais , Antialérgicos/química , Antialérgicos/farmacologia , Células CHO , Cálcio/metabolismo , Quimiocina CCL11 , Quimiocinas CC/farmacologia , Quimiotaxia de Leucócito/efeitos dos fármacos , Cricetinae , Eosinófilos/citologia , Eosinófilos/efeitos dos fármacos , Eosinófilos/metabolismo , Humanos , Técnicas In Vitro , Piperidinas/química , Piperidinas/farmacologia , Receptores CCR3 , Receptores de Quimiocinas/metabolismo , Relação Estrutura-Atividade , Ureia/química , Ureia/farmacologia
9.
Bioorg Med Chem Lett ; 12(13): 1785-9, 2002 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-12067561

RESUMO

CCR3 antagonist leads with IC(50) values in the microM range were converted into low nM binding compounds that displayed in vitro inhibition of human eosinophil chemotaxis induced by human eotaxin. In particular, 4-benzylpiperidin-1-yl-n-propylureas and erythro-3-(4-benzyl-2-(alpha-hydroxyalkyl)piperidin-1-yl)-n-propylureas (obtained via Beak reaction of N-BOC-4-benzylpiperidine) exhibited single digit nanomolar IC(50) values for CCR3.


Assuntos
Antiasmáticos/química , Antiasmáticos/farmacologia , Receptores de Quimiocinas/antagonistas & inibidores , Alquilação , Amidas/química , Amidas/metabolismo , Cálcio/metabolismo , Quimiocina CCL11 , Quimiocinas CC/metabolismo , Quimiotaxia de Leucócito/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Ligantes , Piperidinas/química , Receptores CCR3 , Receptores de Quimiocinas/química , Receptores de Quimiocinas/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade
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