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1.
Protein Sci ; 29(7): 1679-1686, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32239732

RESUMO

Cellular signaling via binding of the cytokines IL-36α, ß, and γ along with binding of the accessory protein IL-36RAcP, to their cognate receptor IL-36R is believed to play a major role in epithelial and immune cell-mediated inflammation responses. Antagonizing the signaling cascade that results from these binding events via a directed monoclonal antibody provides an opportunity to suppress such immune responses. We report here the molecular structure of a complex between an extracellular portion of human IL-36R and a Fab derived from a high affinity anti-IL-36R neutralizing monoclonal antibody at 2.3 Å resolution. This structure, the first of IL-36R, reveals similarities with other structurally characterized IL-1R family members and elucidates the molecular determinants leading to the high affinity binding of the monoclonal antibody. The structure of the complex reveals that the epitope recognized by the Fab is remote from both the putative ligand and accessory protein binding interfaces on IL-36R, suggesting that the functional activity of the antibody is noncompetitive for these binding events.


Assuntos
Anticorpos Monoclonais/química , Fragmentos Fab das Imunoglobulinas/química , Receptores de Interleucina-1/antagonistas & inibidores , Receptores de Interleucina-1/química , Cristalografia por Raios X , Células HEK293 , Humanos , Domínios Proteicos , Estrutura Quaternária de Proteína
2.
Bioorg Med Chem Lett ; 25(3): 581-6, 2015 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-25556092

RESUMO

Through a ligand-based pharmacophore model (S)-proline based compounds were identified as potent cannabinoid receptor 2 (CB2) agonists with high selectivity over the cannabinoid receptor 1 (CB1). Structure-activity relationship investigations for this compound class lead to oxo-proline compounds 21 and 22 which combine an impressive CB1 selectivity profile with good pharmacokinetic properties. In a streptozotocin induced diabetic neuropathy model, 22 demonstrated a dose-dependent reversal of mechanical hyperalgesia.


Assuntos
Isoxazóis/química , Prolina/química , Ácido Pirrolidonocarboxílico/análogos & derivados , Receptor CB2 de Canabinoide/agonistas , Animais , Neuropatias Diabéticas/induzido quimicamente , Neuropatias Diabéticas/tratamento farmacológico , Meia-Vida , Humanos , Isoxazóis/farmacocinética , Isoxazóis/uso terapêutico , Ligantes , Masculino , Microssomos Hepáticos/metabolismo , Prolina/farmacocinética , Prolina/uso terapêutico , Ligação Proteica , Ácido Pirrolidonocarboxílico/química , Ácido Pirrolidonocarboxílico/farmacocinética , Ácido Pirrolidonocarboxílico/uso terapêutico , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Solubilidade , Relação Estrutura-Atividade
3.
Bioorg Med Chem Lett ; 25(3): 575-80, 2015 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-25556098

RESUMO

Computer-aided drug design scaffold hopping strategies were utilized to identify new classes of CB2 agonists when compounds of an established series with low nanomolar potency were challenging to optimize for good drug-like properties. Use of ligand-based design strategies through BI Builder (a tool for de novo design) and PharmShape (a virtual screening software package) approaches led to the discovery of new chemotypes. Specifically, compounds containing azetidine-, proline-, and piperidine-based cores were found to have low nanomolar and picomolar CB2 agonist activities with drug-like properties considered appropriate for early profiling.


Assuntos
Desenho de Fármacos , Receptor CB2 de Canabinoide/agonistas , Desenho Assistido por Computador , Humanos , Ligantes , Microssomos Hepáticos/metabolismo , Ligação Proteica , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Solubilidade , Relação Estrutura-Atividade
4.
Bioorg Med Chem Lett ; 25(3): 587-92, 2015 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-25575658

RESUMO

A novel class of potent cannabinoid receptor 2 (CB2) agonists based on a (S)-piperidine scaffold was identified using ligand-based pharmacophore models. Optimization of solubility and metabolic stability led to the identification of several potent CB2 agonists (e.g., 30) that displayed selectivity over cannabinoid receptor 1 (CB1) and acceptable drug like properties. In rats, compound 30 demonstrated a favorable pharmacokinetic profile and efficacy in a Streptozotocin-induced diabetic neuropathy model, with full reversal of mechanical hyperalgesia.


Assuntos
Ácidos Pipecólicos/química , Piperidinas/química , Receptor CB2 de Canabinoide/agonistas , Tiazinas/química , Animais , Neuropatias Diabéticas/induzido quimicamente , Neuropatias Diabéticas/tratamento farmacológico , Meia-Vida , Humanos , Ligantes , Masculino , Microssomos Hepáticos/metabolismo , Dor/tratamento farmacológico , Ácidos Pipecólicos/farmacocinética , Ácidos Pipecólicos/uso terapêutico , Piperidinas/farmacocinética , Piperidinas/uso terapêutico , Ligação Proteica , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Solubilidade , Relação Estrutura-Atividade , Tiazinas/farmacocinética , Tiazinas/uso terapêutico
5.
PLoS One ; 9(6): e100883, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24967665

RESUMO

GPBAR1 is a G protein-coupled receptor that is activated by certain bile acids and plays an important role in the regulation of bile acid synthesis, lipid metabolism, and energy homeostasis. Recent evidence suggests that GPBAR1 may also have important effects in reducing the inflammatory response through its expression on monocytes and macrophages. To further understand the role of GPBAR1 in inflammation, we generated a novel, selective, proprietary GPBAR1 agonist and tested its effectiveness at reducing monocyte and macrophage activation in vitro and in vivo. We have used this agonist, together with previously described agonists to study agonism of GPBAR1, and shown that they can all induce cAMP and reduce TLR activation-induced cytokine production in human monocytes and monocyte-derived macrophages in vitro. Additionally, through the usage of RNA sequencing (RNA-Seq), we identified a select set of genes that are regulated by GPBAR1 agonism during LPS activation. To further define the in vivo role of GPBAR1 in inflammation, we assessed GPBAR1 expression and found high levels on circulating mouse monocytes. Agonism of GPBAR1 reduced LPS-induced cytokine production in mouse monocytes ex vivo and serum cytokine levels in vivo. Agonism of GPBAR1 also had profound effects in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis, where monocytes play an important role. Mice treated with the GPBAR1 agonist exhibited a significant reduction in the EAE clinical score which correlated with reduced monocyte and microglial activation and reduced trafficking of monocytes and T cells into the CNS. These data confirm the importance of GPBAR1 in controlling monocyte and macrophage activation in vivo and support the rationale for selective agonists of GPBAR1 in the treatment of inflammatory diseases.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Células Mieloides/efeitos dos fármacos , Células Mieloides/imunologia , Receptores Acoplados a Proteínas G/agonistas , Animais , Células CHO , Análise por Conglomerados , Cricetulus , AMP Cíclico , Citocinas/biossíntese , Encefalomielite Autoimune Experimental/tratamento farmacológico , Feminino , Perfilação da Expressão Gênica , Humanos , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Monócitos/metabolismo , Células Mieloides/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo
6.
J Pharmacol Exp Ther ; 348(3): 421-31, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24399854

RESUMO

Bile acids (BAs) and BA receptors, including G protein-coupled bile acid receptor 1 (GPBAR1), represent novel targets for the treatment of metabolic and inflammatory disorders. However, BAs elicit myriad effects on cardiovascular function, although this has not been specifically ascribed to GPBAR1. This study was designed to test whether stimulation of GPBAR1 elicits effects on cardiovascular function that are mechanism based that can be identified in acute ex vivo and in vivo cardiovascular models, to delineate whether effects were due to pathways known to be modulated by BAs, and to establish whether a therapeutic window between in vivo cardiovascular liabilities and on-target efficacy could be defined. The results demonstrated that the infusion of three structurally diverse and selective GPBAR1 agonists produced marked reductions in vascular tone and blood pressure in dog, but not in rat, as well as reflex tachycardia and a positive inotropic response, effects that manifested in an enhanced cardiac output. Changes in cardiovascular function were unrelated to modulation of the levothyroxine/thyroxine axis and were nitric oxide independent. A direct effect on vascular tone was confirmed in dog isolated vascular rings, whereby concentration-dependent decreases in tension that were tightly correlated with reductions in vascular tone observed in vivo and were blocked by iberiotoxin. Compound concentrations in which cardiovascular effects occurred, both ex vivo and in vivo, could not be separated from those necessary for modulation of GPBAR1-mediated efficacy, resulting in project termination. These results are the first to clearly demonstrate direct and potent peripheral arterial vasodilation due to GPBAR1 stimulation in vivo through activation of large conductance Ca(2+) activated potassium channel K(Ca)1.1.


Assuntos
Artérias/efeitos dos fármacos , Receptores Acoplados a Proteínas G/agonistas , Vasodilatação/efeitos dos fármacos , Animais , Artérias/fisiologia , Fator Natriurético Atrial/sangue , Células CHO , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/patologia , Cricetinae , Cricetulus , AMP Cíclico/metabolismo , Citocinas/sangue , Dinitrofluorbenzeno/análogos & derivados , Cães , Endotelina-1/sangue , Humanos , Imidazóis/farmacologia , Técnicas In Vitro , Masculino , Óxido Nítrico/biossíntese , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Tiroxina/sangue , Triazóis/farmacologia
7.
Bioorg Med Chem Lett ; 22(23): 7189-93, 2012 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-23084902

RESUMO

This paper details exploration of a class of triazole-based cathepsin S inhibitors originally reported by Ellman and co-workers. SAR studies involving modifications across the whole inhibitor provide a perspective on the strengths and weaknesses of this class of inhibitors. In addition, we put the unique characteristics of this class of compounds into perspective with other classes of cathepsin S inhibitors.


Assuntos
Amidas/química , Catepsinas/antagonistas & inibidores , Inibidores de Proteases/química , Tiofenos/química , Triazóis/química , Catepsinas/metabolismo , Meia-Vida , Humanos , Microssomos Hepáticos/metabolismo , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacocinética , Ligação Proteica , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/farmacocinética , Triazóis/síntese química , Triazóis/farmacocinética
8.
J Med Chem ; 55(16): 7114-40, 2012 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-22803959

RESUMO

Sodium-hydrogen exchanger isoform 1 (NHE1) is a ubiquitously expressed transmembrane ion channel responsible for intracellular pH regulation. During myocardial ischemia, low pH activates NHE1 and causes increased intracellular calcium levels and aberrant cellular processes, leading to myocardial stunning, arrhythmias, and ultimately cell damage and death. The role of NHE1 in cardiac injury has prompted interest in the development of NHE1 inhibitors for the treatment of heart failure. This report outlines our efforts to identify a compound suitable for once daily, oral administration with low drug-drug interaction potential starting from NHE1 inhibitor sabiporide. Substitution of a piperidine for the piperazine of sabiporide followed by replacement of the pyrrole moiety and subsequent optimization to improve potency and eliminate off-target activities resulted in the identification of N-[4-(1-acetyl-piperidin-4-yl)-3-trifluoromethyl-benzoyl]-guanidine (60). Pharmacological evaluation of 60 revealed a remarkable ability to prevent ischemic damage in an ex vivo model of ischemia reperfusion injury in isolated rat hearts.


Assuntos
Benzamidas/síntese química , Guanidinas/síntese química , Infarto do Miocárdio/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Trocadores de Sódio-Hidrogênio/antagonistas & inibidores , Animais , Benzamidas/química , Benzamidas/farmacologia , Disponibilidade Biológica , Plaquetas/citologia , Plaquetas/efeitos dos fármacos , Linhagem Celular , Permeabilidade da Membrana Celular , Tamanho Celular , Inibidores das Enzimas do Citocromo P-450 , Cães , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Guanidinas/química , Guanidinas/farmacologia , Humanos , Masculino , Membranas Artificiais , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Permeabilidade , Isoformas de Proteínas/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Trocador 1 de Sódio-Hidrogênio , Relação Estrutura-Atividade
9.
Bioorg Med Chem Lett ; 20(12): 3746-9, 2010 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-20471253

RESUMO

The discovery and SAR of a series of beta-aryl substituted pyrrolidine 2H-isoquinolin-1-one inhibitors of Rho-kinase (ROCK) derived from 2 is herein described. SAR studies have shown that aryl groups in the beta-position are optimal for potency. Our efforts focused on improving the ROCK potency of this isoquinolone class of inhibitors which led to the identification of pyrrolidine 32 which demonstrated a 10-fold improvement in aortic ring (AR) potency over 2.


Assuntos
Isoquinolinas/química , Inibidores de Proteínas Quinases/química , Pirrolidinas/síntese química , Quinases Associadas a rho/antagonistas & inibidores , Animais , Aorta/efeitos dos fármacos , Cristalografia por Raios X , Desenho de Fármacos , Hipertensão/tratamento farmacológico , Concentração Inibidora 50 , Isoquinolinas/farmacologia , Estrutura Molecular , Inibidores de Proteínas Quinases/farmacologia , Pirrolidinas/química , Pirrolidinas/farmacologia , Ratos , Relação Estrutura-Atividade
10.
J Chem Inf Model ; 50(2): 274-97, 2010 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-20078034

RESUMO

In this paper, we describe an in silico first principal approach to predict the mutagenic potential of primary aromatic amines. This approach is based on the so-called "nitrenium hypothesis", which was developed by Ford et al. in the early 1990s. This hypothesis asserts that the mutagenic effect for this class of molecules is mediated through the transient formation of a nitrenium ion and that the stability of this cation is correlated with the mutagenic potential. Here we use quantum mechanical calculations at different levels of theory (semiempirical AM1, ab initio HF/3-21G, HF/6-311G(d,p), and DFT/B3LYP/6-311G(d,p)) to compute the stability of nitrenium ions. When applied to a test set of 257 primary aromatic amines, we show that this method can correctly differentiate between Ames active and inactive compounds, and furthermore that it is able to rationalize and predict SAR trends within structurally related chemical series. For this test set, the AM1 nitrenium stability calculations are found to provide a good balance between speed and accuracy, resulting in an overall accuracy of 85%, and sensitivity and specificity of 91% and 72%, respectively. The nitrenium-based predictions are also compared to the commercial software packages DEREK, MULTICASE, and the MOE-Toxicophore descriptor. One advantage of the approach presented here is that the calculation of relative stabilities results in a continuous spectrum of activities and not a simple yes/no answer. This allows us to observe and rationalize subtle trends due to the different electrostatic properties of the organic molecules. Our results strongly indicate that nitrenium ion stability calculations should be used as a complementary approach to assist the medicinal chemist in prioritizing and selecting nonmutagenic primary aromatic amines during preclinical drug discovery programs.


Assuntos
Aminas/química , Aminas/toxicidade , Biologia Computacional , Fenômenos Químicos , Bases de Dados Factuais , Modelos Moleculares , Conformação Molecular , Testes de Mutagenicidade , Software , Relação Estrutura-Atividade , Termodinâmica
11.
Bioorg Med Chem Lett ; 19(9): 2386-91, 2009 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-19356929

RESUMO

An effort aimed at exploring structural diversity in the N-pyrazole-N'-naphthylurea class of p38 kinase inhibitors led to the synthesis and characterization of N-phenyl-N'-naphthylureas. Examples of these compounds displayed excellent inhibition of TNF-alpha production in vitro, as well as efficacy in a mouse model of lipopolysaccharide induced endotoxemia. In addition, perspective is provided on the role of a sulfonamide functionality in defining inhibitor potency.


Assuntos
2-Naftilamina/análogos & derivados , Inibidores de Proteínas Quinases/farmacologia , Ureia/análogos & derivados , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , 2-Naftilamina/química , Animais , Química Orgânica/métodos , Química Farmacêutica/métodos , Cristalografia por Raios X/métodos , Desenho de Fármacos , Concentração Inibidora 50 , Lipopolissacarídeos/metabolismo , Camundongos , Modelos Químicos , Estrutura Molecular , Fator de Necrose Tumoral alfa/metabolismo , Ureia/química
12.
Bioorg Med Chem Lett ; 17(15): 4242-7, 2007 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-17560108

RESUMO

Discovery of the pyrazole-naphthyl urea class of p38 MAP kinase inhibitors typified by the clinical candidate BIRB 796 has encouraged further exploration of this particular scaffold. Modification to the part of the inhibitor that occupies the adenine/ATP binding site has resulted in a new way to obtain potent inhibitors that possess favorable in vitro and in vivo properties.


Assuntos
Adenina/metabolismo , Inibidores de Proteínas Quinases/química , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Sítios de Ligação , Humanos , Modelos Moleculares , Inibidores de Proteínas Quinases/metabolismo , Relação Estrutura-Atividade , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
13.
Mol Cell ; 25(3): 473-81, 2007 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-17289593

RESUMO

Histone lysine methylation has important roles in the organization of chromatin domains and the regulation of gene expression. To analyze its function and modulate its activity, we screened for specific inhibitors against histone lysine methyltransferases (HMTases) using recombinant G9a as the target enzyme. From a chemical library comprising 125,000 preselected compounds, seven hits were identified. Of those, one inhibitor, BIX-01294 (diazepin-quinazolin-amine derivative), does not compete with the cofactor S-adenosyl-methionine, and selectively impairs the G9a HMTase and the generation of H3K9me2 in vitro. In cellular assays, transient incubation of several cell lines with BIX-01294 lowers bulk H3K9me2 levels that are restored upon removal of the inhibitor. Importantly, chromatin immunoprecipitation at several G9a target genes demonstrates reversible reduction of promoter-proximal H3K9me2 in inhibitor-treated mouse ES cells and fibroblasts. Our data identify a biologically active HMTase inhibitor that allows for the transient modulation of H3K9me2 marks in mammalian chromatin.


Assuntos
Azepinas/farmacologia , Inibidores Enzimáticos/farmacologia , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Histonas/metabolismo , Quinazolinas/farmacologia , Animais , Linhagem Celular , Histona Metiltransferases , Histona-Lisina N-Metiltransferase/metabolismo , Histona-Lisina N-Metiltransferase/fisiologia , Histonas/efeitos dos fármacos , Humanos , Lisina/química , Lisina/metabolismo , Metilação , Camundongos , Regiões Promotoras Genéticas , Proteínas Metiltransferases
14.
J Biol Chem ; 280(7): 6130-7, 2005 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-15525646

RESUMO

Pim-1 kinase is a member of a distinct class of serine/threonine kinases consisting of Pim-1, Pim-2, and Pim-3. Pim kinases are highly homologous to one another and share a unique consensus hinge region sequence, ER-PXPX, with its two proline residues separated by a non-conserved residue, but they (Pim kinases) have <30% sequence identity with other kinases. Pim-1 has been implicated in both cytokine-induced signal transduction and the development of lymphoid malignancies. We have determined the crystal structures of apo Pim-1 kinase and its AMP-PNP (5'-adenylyl-beta,gamma-imidodiphosphate) complex to 2.1-angstroms resolutions. The structures reveal the following. 1) The kinase adopts a constitutively active conformation, and extensive hydrophobic and hydrogen bond interactions between the activation loop and the catalytic loop might be the structural basis for maintaining such a conformation. 2) The hinge region has a novel architecture and hydrogen-bonding pattern, which not only expand the ATP pocket but also serve to establish unambiguously the alignment of the Pim-1 hinge region with that of other kinases. 3) The binding mode of AMP-PNP to Pim-1 kinase is unique and does not involve a critical hinge region hydrogen bond interaction. Analysis of the reported Pim-1 kinase-domain structures leads to a hypothesis as to how Pim kinase activity might be regulated in vivo.


Assuntos
Adenilil Imidodifosfato/metabolismo , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/química , Proteínas Proto-Oncogênicas/metabolismo , Adenilil Imidodifosfato/química , Sequência de Aminoácidos , Apoproteínas/química , Apoproteínas/metabolismo , Domínio Catalítico , Cristalografia por Raios X , Ativação Enzimática , Humanos , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Dobramento de Proteína , Proteínas Proto-Oncogênicas c-pim-1 , Relação Estrutura-Atividade
15.
Bioorg Med Chem Lett ; 13(18): 3101-4, 2003 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-12941343

RESUMO

BIRB 796, a member of the N-pyrazole-N'-naphthly urea class of p38MAPK inhibitors, binds to the kinase with both slow association and dissociation rates. Prior to binding, the kinase undergoes a reorganization of the activation loop exposing a critical binding domain. We demonstrate that, independent of the loop movement, association rates are governed by low energy conformations of the inhibitor and polar functionality on the tolyl ring. As anticipated, the dissociation rates of the inhibitors from the kinase are slowed by lipophilic and hydrogen bond interactions. The value of structure-kinetic relationships (SKR) in drug design is discussed.


Assuntos
Inibidores Enzimáticos/química , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Naftalenos/química , Pirazóis/química , Doenças Autoimunes/tratamento farmacológico , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Concentração Inibidora 50 , Cinética , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/química , Naftalenos/farmacologia , Ligação Proteica , Estrutura Terciária de Proteína , Pirazóis/farmacologia , Relação Estrutura-Atividade , Proteínas Quinases p38 Ativadas por Mitógeno
16.
Nat Struct Biol ; 9(4): 268-72, 2002 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11896401

RESUMO

The p38 MAP kinase plays a crucial role in regulating the production of proinflammatory cytokines, such as tumor necrosis factor and interleukin-1. Blocking this kinase may offer an effective therapy for treating many inflammatory diseases. Here we report a new allosteric binding site for a diaryl urea class of highly potent and selective inhibitors against human p38 MAP kinase. The formation of this binding site requires a large conformational change not observed previously for any of the protein Ser/Thr kinases. This change is in the highly conserved Asp-Phe-Gly motif within the active site of the kinase. Solution studies demonstrate that this class of compounds has slow binding kinetics, consistent with the requirement for conformational change. Improving interactions in this allosteric pocket, as well as establishing binding interactions in the ATP pocket, enhanced the affinity of the inhibitors by 12,000-fold. One of the most potent compounds in this series, BIRB 796, has picomolar affinity for the kinase and low nanomolar inhibitory activity in cell culture.


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/química , Sítio Alostérico , Motivos de Aminoácidos , Linhagem Celular , Cristalografia por Raios X , Inibidores Enzimáticos/metabolismo , Humanos , Concentração Inibidora 50 , Cinética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Modelos Moleculares , Naftalenos/química , Naftalenos/metabolismo , Naftalenos/farmacologia , Ligação Proteica , Conformação Proteica , Pirazóis/química , Pirazóis/metabolismo , Pirazóis/farmacologia , Especificidade por Substrato , Fatores de Tempo , Proteínas Quinases p38 Ativadas por Mitógeno
17.
Angew Chem Int Ed Engl ; 38(10): 1409-1411, 1999 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-29711571

RESUMO

Despite its preferred equatorial conformation in the solid state and in solution, the cis,cis-trispiro ether 1 binds readily and strongly to lithium ions. The 2:1 sandwich complex 2 is initially formed and transformed progressively into the 1:1 species 3 upon the addition of more LiClO4 .

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