RESUMO
Bromodomain and extra-terminal domain (BET) protein plays an important role in epigenetic regulation, and the regulation of disruption contributes to the pathogenesis of cancer and inflammatory disease. With the goal of discovering novel BET inhibitors, especially BRD4 inhibitors, we designed and synthesized several compounds starting from our previously reported pyrido-benzodiazepinone derivative 4 to enhance BRD4 inhibitory activity while avoiding hERG inhibition. Molecular docking studies and structure-activity relationship studies led to the identification of 9-fluorobenzo[f]pyrido[4,3-b][1,4]oxazepin-10-one derivative 43, which exhibited potent BRD4 inhibitory activity with excellent potency in imiquimod-induced psoriasis model mice.
Assuntos
Proteínas do Tecido Nervoso/antagonistas & inibidores , Oxazepinas/química , Oxazepinas/farmacologia , Receptores de Superfície Celular/antagonistas & inibidores , Animais , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , Modelos Moleculares , Estrutura Molecular , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/classificação , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Oxazepinas/administração & dosagem , Oxazepinas/síntese química , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Relação Estrutura-Atividade , Fatores de Transcrição/classificação , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
We investigated the autofluorescence of tomato surface tissues during overripening at 25 °C for 13 days. Microscopic images and fluorescence spectra of tissues, including the epidermis and cuticle, were examined (excitation at 360 nm), revealing that the autofluorescence changes were related to the epidermis, particularly the fluorophores in the cuticle.
Assuntos
Epiderme/química , Fluorescência , Corantes Fluorescentes/química , Solanum lycopersicum/química , Espectrometria de Fluorescência , Propriedades de SuperfícieRESUMO
Formyl peptide receptor 2 (FPR2) agonists can stimulate resolution of inflammation and may have utility for treatment of diseases caused by chronic inflammation, including heart failure. We report the discovery of a potent and selective FPR2 agonist and its evaluation in a mouse heart failure model. A simple linear urea with moderate agonist activity served as the starting point for optimization. Introduction of a pyrrolidinone core accessed a rigid conformation that produced potent FPR2 and FPR1 agonists. Optimization of lactam substituents led to the discovery of the FPR2 selective agonist 13c, BMS-986235/LAR-1219. In cellular assays 13c inhibited neutrophil chemotaxis and stimulated macrophage phagocytosis, key end points to promote resolution of inflammation. Cardiac structure and functional improvements were observed in a mouse heart failure model following treatment with BMS-986235/LAR-1219.
Assuntos
Pirrolidinonas/química , Receptores de Formil Peptídeo/agonistas , Receptores de Lipoxinas/agonistas , Animais , Quimiotaxia/efeitos dos fármacos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Células HEK293 , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/prevenção & controle , Humanos , Macrófagos/citologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Microssomos Hepáticos/metabolismo , Neutrófilos/citologia , Neutrófilos/fisiologia , Fagocitose/efeitos dos fármacos , Pirrolidinonas/metabolismo , Pirrolidinonas/farmacologia , Pirrolidinonas/uso terapêutico , Receptores de Formil Peptídeo/genética , Receptores de Formil Peptídeo/metabolismo , Receptores de Lipoxinas/genética , Receptores de Lipoxinas/metabolismo , Relação Estrutura-AtividadeRESUMO
A scaffold-hopping strategy towards a new pyrazolo[1,5-a]pyridine based core using molecular hybridization of two structurally distinct EP1 antagonists, followed by structure-activity relationship-guided optimization, resulted in the identification of potent EP1 antagonists exemplified by 4c, 4f, and 4j, which were shown to reduce pathological intravesical pressure in rats when administered at 1mg/kg iv.
Assuntos
Descoberta de Drogas , Pirazóis/farmacologia , Piridinas/farmacologia , Receptores de Prostaglandina E Subtipo EP1/antagonistas & inibidores , Animais , Relação Dose-Resposta a Droga , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Piridinas/síntese química , Piridinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
Herein we described the design, synthesis and evaluation of a novel series of benzo[d]thiazole derivatives toward an orally active EP1 antagonist. Lead generation studies provided benzo[d]thiazole core from the four designed scaffolds. Optimization of this scaffold in terms of EP1 antagonist potency and ligand-lipophilicity efficiency (LLE; pIC50-clogP) led to a 1,2,3,6-tetrahydropyridyl-substituted benzo[d]thiazole derivative, 7r (IC50 1.1nM; LLE 4.7), which showed a good pharmacological effect when administered intraduodenally in a 17-phenyl trinor-PGE2 (17-PTP)-induced overactive bladder model in rats.
Assuntos
Benzotiazóis/farmacologia , Receptores de Prostaglandina E Subtipo EP1/antagonistas & inibidores , Bexiga Urinária Hiperativa/tratamento farmacológico , Administração Oral , Animais , Benzotiazóis/administração & dosagem , Benzotiazóis/química , Dinoprostona/análogos & derivados , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ligantes , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Bexiga Urinária Hiperativa/induzido quimicamenteRESUMO
Novel pyrazolo[1,5-a]pyridine derivatives were designed, synthesized and evaluated as orally active EP1 antagonists for the treatment of overactive bladder. Matched molecular pair analysis (MMPA) allowed the design of a new series of pyrazolo[1,5-a]pyridine derivatives 4-6. Structure-activity relationships (SAR) studies of 4-6 were performed, leading to identification of the nanomolar-level EP1 antagonist 4c, which exhibited good pharmacological effect through intraduodenal (id) administration in a 17-phenyltrinor prostaglandin E2-induced bladder contraction model in rats.
Assuntos
Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Receptores de Prostaglandina E Subtipo EP1/antagonistas & inibidores , Animais , Linhagem Celular , Masculino , Pirazóis/síntese química , Pirazóis/farmacocinética , Piridinas/síntese química , Piridinas/farmacocinética , Ratos Wistar , Relação Estrutura-Atividade , Bexiga Urinária Hiperativa/tratamento farmacológicoRESUMO
We attempted to optimize sulfonamide-based non-alkyne LpxC inhibitors by focusing on improvements in enzyme inhibitory and antibacterial activity. It was discovered that inhibitors possessing 2-aryl benzofuran as a hydrophobe exhibited good activity. In particular, compound 21 displayed impressive antibacterial activity (E. coli MIC=0.063µg/mL, K. pneumoniae MIC=0.5µg/mL, and P. aeruginosa MIC=0.5µg/mL), and is a promising lead for further exploration as an antibacterial agent.
Assuntos
Amidoidrolases/antagonistas & inibidores , Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Sulfonamidas/farmacologia , Antibacterianos/química , Farmacorresistência Bacteriana , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Sulfonamidas/químicaRESUMO
Herein we report a scaffold-hopping approach to identify a new scaffold with a zinc binding headgroup. Structural information was used to give novel oxazolidinone-based LpxC inhibitors. In particular, the most potent compound, 23j, showed a low efflux ratio, nanomolar potencies against E. coli LpxC enzyme, and excellent antibacterial activity against E. coli and K. pneumoniae. Computational docking was used to predict the interaction between 23j and E. coli LpxC, suggesting that the interactions with C207 and C63 contribute to the strong activity. These results provide new insights into the design of next-generation LpxC inhibitors.
RESUMO
The molecular pharmacology of the G protein-coupled receptors for sphingosine 1-phosphate (S1P) provides important insight into established and new therapeutic targets. A new, potent bitopic S1P3 antagonist, SPM-354, with in vivo activity, has been used, together with S1P3-knockin and S1P3-knockout mice to define the spatial and functional properties of S1P3 in regulating cardiac conduction. We show that S1P3 is a key direct regulator of cardiac rhythm both in vivo and in isolated perfused hearts. 2-Amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol in vivo and S1P in isolated hearts induced a spectrum of cardiac effects, ranging from sinus bradycardia to complete heart block, as measured by a surface electrocardiogram in anesthetized mice and in volume-conducted Langendorff preparations. The agonist effects on complete heart block are absent in S1P3-knockout mice and are reversed in wild-type mice with SPM-354, as characterized and described here. Homologous knockin of S1P3-mCherry is fully functional pharmacologically and is strongly expressed by immunohistochemistry confocal microscopy in Hyperpolarization Activated Cyclic Nucleotide Gated Potassium Channel 4 (HCN4)-positive atrioventricular node and His-Purkinje fibers, with relative less expression in the HCN4-positive sinoatrial node. In Langendorff studies, at constant pressure, SPM-354 restored sinus rhythm in S1P-induced complete heart block and fully reversed S1P-mediated bradycardia. S1P3 distribution and function in the mouse ventricular cardiac conduction system suggest a direct mechanism for heart block risk that should be further studied in humans. A richer understanding of receptor and ligand usage in the pacemaker cells of the cardiac system is likely to be useful in understanding ventricular conduction in health, disease, and pharmacology.
Assuntos
Bloqueio Cardíaco/tratamento farmacológico , Bloqueio Cardíaco/genética , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Receptores de Lisoesfingolipídeo/antagonistas & inibidores , Receptores de Lisoesfingolipídeo/genética , Animais , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Bloqueio Cardíaco/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Esfingosina-1-FosfatoRESUMO
We previously identified KCA-1490 [(-)-6-(7-methoxy-2-trifluoromethyl-pyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone], a dual PDE3/4 inhibitor. In the present study, we found highly potent selective PDE4 inhibitors derived from the structure of KCA-1490. Among them, N-(3,5-dichloropyridin-4-yl)-7-methoxy-2-(trifluoromethyl)pyrazolo[1,5-a]pyridine-4-carboxamide (2a) had good anti-inflammatory effects in an animal model.
Assuntos
Anti-Inflamatórios , Desenho de Fármacos , Inibidores da Fosfodiesterase 4 , Pirazóis/síntese química , Piridinas , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Ativação Enzimática/efeitos dos fármacos , Concentração Inibidora 50 , Modelos Animais , Estrutura Molecular , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Piridinas/síntese química , Piridinas/química , Piridinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
AX10479, the phenyl amide of 4-hydroxy-8-methanesulfonylamino-quinoline-2-carboxylic acid, was identified as a Zn(2+)-dependent, 27nM inhibitor of human plasma Lp-PLA(2). Structure-activity relationship studies focused on the AX10479 2-phenylamide group identified equipotent cycloaliphatic amides, an enantioselective preference for chiral amides, and phenyl substitution patterns (e.g., 2-methyl-3-fluoro) that increased potency.
Assuntos
1-Alquil-2-acetilglicerofosfocolina Esterase/antagonistas & inibidores , Amidas/farmacologia , Quinolinas/farmacologia , Amidas/síntese química , Amidas/química , Humanos , Quinolinas/síntese química , Quinolinas/química , Estereoisomerismo , Relação Estrutura-Atividade , Zinco/químicaRESUMO
(-)-6-(7-Methoxy-2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (KCA-1490) exhibits moderate dual PDE3/4-inhibitory activity and promises as a combined bronchodilatory/anti-inflammatory agent. N-alkylation of the pyridazinone ring markedly enhances potency against PDE4 but suppresses PDE3 inhibition. Addition of a 6-aryl-4,5-dihydropyridazin-3(2H)-one extension to the N-alkyl group facilitates both enhancement of PDE4-inhibitory activity and restoration of potent PDE3 inhibition. Both dihydropyridazinone rings, in the core and extension, can be replaced by achiral 4,4-dimethylpyrazolone subunits and the core pyrazolopyridine by isosteric bicyclic heteroaromatics. In combination, these modifications afford potent dual PDE3/4 inhibitors that suppress histamine-induced bronchoconstriction in vivo and exhibit promising anti-inflammatory activity via intratracheal administration.
Assuntos
Anti-Inflamatórios/química , Broncodilatadores/química , Inibidores da Fosfodiesterase 3/química , Inibidores da Fosfodiesterase 4/química , Administração por Inalação , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Líquido da Lavagem Broncoalveolar/citologia , Broncodilatadores/síntese química , Broncodilatadores/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Desenho de Fármacos , Leucócitos/efeitos dos fármacos , Inibidores da Fosfodiesterase 3/síntese química , Inibidores da Fosfodiesterase 3/farmacologia , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/farmacologia , Ligação Proteica , Piridazinas/química , Piridinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
Sphingosine 1-phosphate (S1P) is a lysophospholipid signaling molecule that regulates important biological functions, including lymphocyte trafficking and vascular development, by activating G protein-coupled receptors for S1P, namely, S1P(1) through S1P(5). Here, we map the S1P(3) binding pocket with a novel allosteric agonist (CYM-5541), an orthosteric agonist (S1P), and a novel bitopic antagonist (SPM-242). With a combination of site-directed mutagenesis, ligand competition assay, and molecular modeling, we concluded that S1P and CYM-5541 occupy different chemical spaces in the ligand binding pocket of S1P(3). CYM-5541 allowed us to identify an allosteric site where Phe263 is a key gate-keeper residue for its affinity and efficacy. This ligand lacks a polar moiety, and the novel allosteric hydrophobic pocket permits S1P(3) selectivity of CYM-5541 within the highly similar S1P receptor family. However, a novel S1P(3)-selective antagonist, SPM-242, in the S1P(3) pocket occupies the ligand binding spaces of both S1P and CYM-5541, showing its bitopic mode of binding. Therefore, our coordinated approach with biochemical data and molecular modeling, based on our recently published S1P(1) crystal structure data in a highly conserved set of related receptors with a shared ligand, provides a strong basis for the successful optimization of orthosteric, allosteric, and bitopic modulators of S1P(3).
Assuntos
Receptores de Lisoesfingolipídeo/metabolismo , Sítio Alostérico , Animais , Células CHO , Cricetinae , Cricetulus , Ligantes , Modelos Moleculares , Fosforilação , Ensaio Radioligante , Receptores de Lisoesfingolipídeo/antagonistas & inibidoresRESUMO
(-)-6-(7-Methoxy-2-trifluoromethylpyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone (KCA-1490) is a dual PDE3/4 inhibitor that exhibits potent combined bronchodilatory and anti-inflammatory activity. Here we show that a 4,4-dimethylpyrazolone subunit serves as an effective surrogate for the 5-methyl-4,5-dihydropyridazin-3(2H)-one ring of KCA-1490 whilst lacking a stereogenic centre. The 2- and 7-substituents in the pyrazolo[1,5-a]pyridine subunit markedly influence the PDE-inhibitory profile and can be adjusted to afford either potent PDE4-selective inhibitors or dual PDE3/4 inhibitors. A survey of bicyclic heteroaromatic replacements for the pyrazolo[1,5-a]pyridine allowed further refinement of the inhibitory profile and identified 3-(8-methoxy-2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)-4,4-dimethyl-1H-pyrazol-5(4H)-one as an orally active, achiral KCA-1490 analog with well-balanced dual PDE3/4-inhibitory activity.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Desenho de Fármacos , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/farmacologia , Pirazolonas/química , Piridazinas/farmacologia , Piridinas/farmacologia , Relação Dose-Resposta a Droga , Modelos Moleculares , Estrutura Molecular , Inibidores de Fosfodiesterase/química , Piridazinas/síntese química , Piridazinas/química , Piridinas/síntese química , Piridinas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
(-)-6-(7-Methoxy-2-trifluoromethylpyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone (KCA-1490) is a dual PDE3/4 inhibitor that exhibits potent combined bronchodilatory and anti-inflammatory activity. A survey of potential bicyclic heteroaromatic replacement subunits for the pyrazolo[1,5-a]pyridine core of KCA-1490 has identified the 4-methoxy-2-(trifluoromethyl)benzo[d]thiazol-7-yl and 8-methoxy-2-(trifluoromethyl)quinolin-5-yl analogues as dual PDE3/4-inhibitory compounds that potently suppress histamine-induced bronchoconstriction and exhibit anti-inflammatory activity in vivo.
Assuntos
Inibidores da Fosfodiesterase 3/química , Inibidores da Fosfodiesterase 3/farmacologia , Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/farmacologia , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Broncoconstrição/efeitos dos fármacos , Broncodilatadores/síntese química , Broncodilatadores/química , Broncodilatadores/farmacologia , Desenho de Fármacos , Humanos , Modelos Moleculares , Inibidores da Fosfodiesterase 3/síntese química , Inibidores da Fosfodiesterase 4/síntese química , Piridinas/síntese química , Piridinas/química , Piridinas/farmacologia , Relação Estrutura-AtividadeRESUMO
An improved method for 4,4-dimethylpyrazolone synthesis with t-butylcarbazate was described. The applicability of this method to dihydropyridazinone formation was demonstrated. This method is useful for suppressing the side reaction caused by the high nucleophilicity of hydrazine.
Assuntos
Pirazolonas/síntese química , Piridazinas/síntese química , Técnicas de Química Analítica , Hidrazinas/química , Espectroscopia de Ressonância Magnética , Pirazolonas/química , Piridazinas/químicaRESUMO
AX10185, the phenyl amide of xanthurenic acid, was found to be a sub-100nM inhibitor of Lp-PLA(2). However, in the presence of EDTA the inhibitory activity of AX10185 was extinguished while the enzymatic activity of Lp-PLA(2) did not change. Subsequent metal screening experiments determined the inhibition to be Zn(2+) dependent. Structure-activity relationship studies indicated the presence of the 4-hydroxy group to be critical and selected substituted phenyl, polycyclic, and cycloaliphatic amides of xanthurenic acid to be well tolerated.
Assuntos
1-Alquil-2-acetilglicerofosfocolina Esterase/antagonistas & inibidores , Amidas/química , Inibidores Enzimáticos/farmacologia , Compostos Organometálicos/farmacologia , Xanturenatos/química , Zinco/química , 1-Alquil-2-acetilglicerofosfocolina Esterase/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Relação Estrutura-AtividadeRESUMO
The design, synthesis, and evaluation of 6-6-7 tricyclic quinolones containing the strained spirocycle moiety aiming at the GSK-3ß inhibitor were described. Among the synthesized compounds, 44, having a cyclobutane ring on a spirocycle, showed excellent GSK-3ß inhibitory activity in both cell-free and cell-based assays (IC(50) = 36nM, EC(50) = 3.2µM, respectively). Additionally, 44 decreased the plasma glucose concentration dose-dependently after an oral glucose tolerance test in mice.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Quinolonas/química , Quinolonas/farmacologia , Animais , Diabetes Mellitus Tipo 2/enzimologia , Desenho de Fármacos , Teste de Tolerância a Glucose , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Células Hep G2 , Humanos , Masculino , Camundongos , Modelos Moleculares , Quinolonas/síntese química , Quinolonas/farmacocinética , Compostos de Espiro/síntese química , Compostos de Espiro/química , Compostos de Espiro/farmacocinética , Compostos de Espiro/farmacologiaRESUMO
We previously disclosed tricylic, 6-carboxylic acid-bearing 4-quinolones as GSK-3ß inhibitors. Herein we discuss the optimization of this series to yield a series of more potent 6-nitrile analogs with insignificant anti-microbial activity. Finally, kinase profiling indicated that members of this class were highly specific GSK-3 inhibitors.
Assuntos
Antibacterianos/farmacologia , Inibidores Enzimáticos/farmacologia , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Nitrilas/química , Quinolizinas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Escherichia coli/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta , Testes de Sensibilidade Microbiana , Estrutura Molecular , Quinolizinas/síntese química , Quinolizinas/química , Staphylococcus aureus/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The synthesis, GSK-3ß inhibitory activity, and anti-microbial activity of bicyclic and tricyclic derivatives of the 5,7-diamino-6-fluoro-4-quinolone-3-carboxylic acid scaffold were studied. Kinase selectivity profiling indicated that members of this class were potent and highly selective GSK-3 inhibitors.