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1.
Chem Commun (Camb) ; 56(3): 415-418, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31821393

RESUMO

We report a novel 1,2-catechol based radioiodinated precursor for radioiodination of bicyclo[6.1.0]nonyne (BCN) installed biologically active molecules using a strain-promoted oxidation-controlled cyclooctyne-1,2-quinone cycloaddition reaction (SPOCQ) under ambient conditions. Compared to the reported methodologies, the new strategy demonstrates some clear advantages, including high in vitro and in vivo stability, high radiochemical yield, and exceptionally fast reaction kinetics at micro-molar concentration.


Assuntos
Reação de Cicloadição , Quinonas/química , Compostos Radiofarmacêuticos/química , Animais , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Catecóis/química , Coração/diagnóstico por imagem , Radioisótopos do Iodo/química , Marcação por Isótopo , Cinética , Camundongos , Camundongos Endogâmicos ICR , Oxirredução , Compostos Radiofarmacêuticos/síntese química , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único
2.
Org Biomol Chem ; 17(22): 5615-5632, 2019 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-31120090

RESUMO

Routes to bicyclic tetramates derived from cysteine permitting ready incorporation of functionality at two different points around the periphery of a heterocyclic skeleton are reported. This has enabled the identification of systems active against Gram-positive bacteria, some of which show gyrase and RNA polymerase inhibitory activity. In particular, tetramates substituted with glycosyl side chains, chosen to impart polarity and aqueous solubility, show high antibacterial activity coupled with modest gyrase/polymerase activity in two cases. An analysis of physicochemical properties indicates that the antibacterially active tetramates generally occupy physicochemical space with MW of 300-600, clog D7.4 of -2.5 to 4 and rel. PSA of 11-22%. This work demonstrates that biologically active 3D libraries are readily available by manipulation of a tetramate skeleton.


Assuntos
Antibacterianos/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Cisteína/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Cisteína/química , Testes de Sensibilidade Microbiana , Estrutura Molecular
3.
Nat Prod Rep ; 36(2): 263-288, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30215657

RESUMO

Covering: January 2012 to January 2018 Sesterterpenoids are a small family of terpenes that often possess intriguing biological profiles and complicated chemical structures. Their total syntheses are usually remarkably challenging, requiring methodological and strategic innovation. In this review, we summarize and discuss the total syntheses of sesterterpenoids published during the coverage period, and the key chemical transformations are highlighted.


Assuntos
Terpenos/síntese química , 4-Butirolactona/análogos & derivados , 4-Butirolactona/síntese química , Compostos Bicíclicos com Pontes/síntese química , Estrutura Molecular , Sesquiterpenos/síntese química , Sesterterpenos/síntese química
4.
Bioorg Med Chem ; 27(2): 338-342, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30545734

RESUMO

Isocarbacyclin is a valuable synthetic analogue of prostacyclin with potential neuroprotective effects for the treatment of ischemic stroke. Herein, we describe the synthesis of isocarbacyclin and bicyclic analogues in only 7-10 steps, with the ω-side chain diversified at a late stage. A combination of new reaction design, function-oriented synthesis, and late-stage diversification led to a series of compounds that were tested for their neuroprotective activities. Efforts toward the synthesis of tricyclic analogues of isocarbacyclin, using the same combination of metal-catalyzed reactions, is also described.


Assuntos
Compostos Bicíclicos com Pontes/farmacologia , Epoprostenol/análogos & derivados , Fármacos Neuroprotetores/farmacologia , Animais , Isquemia Encefálica/tratamento farmacológico , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Epoprostenol/síntese química , Epoprostenol/química , Epoprostenol/farmacologia , Camundongos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Estereoisomerismo , Acidente Vascular Cerebral/tratamento farmacológico
5.
Chemistry ; 25(14): 3496-3500, 2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30589135

RESUMO

The PYR/PYL/RCAR protein families have recently emerged as receptors of the phytohormone abscisic acid (ABA, 1), which regulates plant responses to environmental stress. These families have multiple members with different physiological actions, and so selective agonists or antagonists are needed both as tools to elucidate functional differences and as lead compounds for agrochemicals. We previously identified RK460 (rac-3 a) as a PYR1-selective antagonist, and showed that it possesses five stereocenters on a 6,5-cis-bicyclo skeleton. Here, we synthesized all the stereoisomers of RK460 and evaluated their activity towards a panel of receptors. Relative stereochemistry as well as absolute stereochemistry was important for selective action.


Assuntos
Ácido Abscísico/metabolismo , Proteínas de Arabidopsis/antagonistas & inibidores , Arabidopsis/efeitos dos fármacos , Compostos Bicíclicos com Pontes/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Reguladores de Crescimento de Planta/metabolismo , Receptores de Superfície Celular/antagonistas & inibidores , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Reguladores de Crescimento de Planta/síntese química , Reguladores de Crescimento de Planta/química , Receptores de Superfície Celular/metabolismo , Estereoisomerismo
6.
Bioorg Med Chem Lett ; 29(2): 248-251, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30501964

RESUMO

An innovative and efficient reagent- and scaffold-based diversity oriented synthesis (DOS) of a fragment set was developed for fragment-based drug discovery (FBDD) programs. Twelve diverse, functionalized and bicyclic scaffolds were rapidly accessed by adopting a convenient synthetic toolkit around three privileged azine cores in order to effectively modulate biomolecules. These structures are characterized by both key motifs for interacting with diverse biological targets via hydrogen bonds and useful points of growth for subsequent fragment optimization.


Assuntos
Compostos Azo/síntese química , Compostos Bicíclicos com Pontes/síntese química , Compostos Azo/química , Compostos Bicíclicos com Pontes/química , Descoberta de Drogas , Ligações de Hidrogênio , Estrutura Molecular
7.
Angew Chem Int Ed Engl ; 57(45): 14921-14925, 2018 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-30199596

RESUMO

The analysis of volatiles released by marine Salinispora bacteria uncovered a new class of natural compounds displaying an unusual bicyclic [3.1.0]-lactone skeleton. Although only sub-µg quantities of the compounds were available, the combination of analytical methods, computational spectroscopy, and synthesis allowed unambiguous structural identification of the compounds, called salinilactones, without the need for isolation. Orthogonal hyphenated methods, GC/MS and solid-phase GC/IR allowed to propose a small set of structures consistent with the data. A candidate structure was selected by comparison of DFT-calculated IR spectra and the experimental IR-spectrum. Synthesis confirmed the structure and absolute configuration of three bicyclic lactones, salinilactones A-C. The salinilactones are structurally closely related to the A-factor class of compounds, autoregulators from streptomycete bacteria. They exhibited inhibitory activity against Salinispora and Streptomyces strains.


Assuntos
Actinobacteria/química , Lactonas/química , 4-Butirolactona/análogos & derivados , 4-Butirolactona/química , Actinobacteria/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Cromatografia Gasosa-Espectrometria de Massas , Lactonas/síntese química , Lactonas/farmacologia , Espectrofotometria Infravermelho , Streptomyces/química , Streptomyces/efeitos dos fármacos
8.
Chemistry ; 24(72): 19250-19257, 2018 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-30255960

RESUMO

The chemical synthesis of a bicycle inspired by the natural lasso peptide sungsanpin using a combination of solid-phase and in-solution chemistries is described. The bicyclic-derived topoisomer was designed by introducing a covalent linkage between the ring and the loop, which allowed the tying of these two parts of the peptide, rendering the bicyclic structure. Several structural techniques, such as MS fragmentation, ion-mobility and NMR spectroscopic analysis were used to characterize the bicycle. Ion-mobility spectroscopy studies revealed that it showed lasso-like behavior. Its 3D structure was predicted on the basis of the NMR restraints. In addition, the high proteolytic and thermal stability of the bicycle potentially make it a suitable scaffold for epitope grafting.


Assuntos
Compostos Bicíclicos com Pontes/química , Peptídeos/química , Compostos Bicíclicos com Pontes/síntese química , Modelos Moleculares , Peptídeos/síntese química , Conformação Proteica , Estabilidade Proteica
9.
Bioorg Med Chem Lett ; 28(15): 2605-2610, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-29970308

RESUMO

We describe the design, synthesis, X-ray studies, and biological evaluation of novel BACE1 inhibitors containing bicyclic isoxazoline carboxamides as the P3 ligand in combination with methyl cysteine, methylsulfonylalanine and Boc-amino alanine as P2 ligands. Inhibitor 3a displayed a BACE1 Ki value of 10.9 nM and EC50 of 343 nM. The X-ray structure of 3a bound to the active site of BACE1 was determined at 2.85 Šresolution. The structure revealed that the major molecular interactions between BACE1 and the bicyclic tetrahydrofuranyl isoxazoline heterocycle are van der Waals in nature.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Alanina/análogos & derivados , Alanina/química , Amidas/química , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Compostos Bicíclicos com Pontes/síntese química , Ácidos Carboxílicos/química , Domínio Catalítico , Cristalografia por Raios X , Cisteína/análogos & derivados , Cisteína/química , Humanos , Isoxazóis/química , Estrutura Molecular , Inibidores de Proteases/síntese química
11.
Chem Commun (Camb) ; 54(56): 7810-7813, 2018 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-29946609

RESUMO

Here we report the 18F labeling of a prostate specific membrane antigen (PSMA) ligand via a strain promoted oxa-dibenzocyclooctyne (ODIBO)- or bicyclo[6.1.0]nonyne (BCN)-azide reaction. Although ODIBO reacts with azide 20 fold faster than BCN, in vivo PET imaging suggests that 18F-BCN-azide-PSMA demonstrated much higher tumor uptake and a much higher tumor to background contrast.


Assuntos
Alquinos/química , Antígenos de Superfície/metabolismo , Azidas/química , Compostos Bicíclicos com Pontes/metabolismo , Ciclo-Octanos/metabolismo , Glutamato Carboxipeptidase II/metabolismo , Hidrocarbonetos Fluorados/metabolismo , Compostos Radiofarmacêuticos/metabolismo , Animais , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Ciclo-Octanos/síntese química , Ciclo-Octanos/química , Ciclo-Octanos/farmacologia , Dipeptídeos/metabolismo , Radioisótopos de Flúor , Compostos Heterocíclicos com 1 Anel/metabolismo , Humanos , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/química , Hidrocarbonetos Fluorados/farmacologia , Interações Hidrofóbicas e Hidrofílicas , Cinética , Ligantes , Masculino , Camundongos , Tomografia por Emissão de Pósitrons , Neoplasias da Próstata/diagnóstico por imagem , Ligação Proteica , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Bioorg Med Chem ; 26(12): 3345-3351, 2018 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-29748146

RESUMO

Bicyclo[3,3,1]non-2-ene was used as a novel three-dimensional skeleton for the design and synthesis of hypoxia-inducible factor (HIF)-1 inhibitors. Among the compounds synthesized, compound 4b was found to be a potent inhibitor of HIF-1α protein accumulation under hypoxia and inhibited HIF-1α transcriptional activity in HeLa (human cervical carcinoma) cells (half maximal inhibitory concentration [IC50] = 3.0 µM). The inhibition of HIF-1α accumulation induced by compound 4b was attenuated by treating the cells with MG132, a proteasome inhibitor, in a concentration-dependent manner, indicating that the compound 4b induces oxygen-independent proteasomal degradation of HIF-1α.


Assuntos
Compostos Bicíclicos com Pontes/química , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/farmacologia , Desenho de Drogas , Células HeLa , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Leupeptinas/farmacologia , Complexo de Endopeptidases do Proteassoma/química , Complexo de Endopeptidases do Proteassoma/metabolismo , Transcrição Genética/efeitos dos fármacos
13.
J Med Chem ; 61(7): 2823-2836, 2018 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-29517911

RESUMO

Plasma kallikrein, a member of the kallikrein-kinin system, catalyzes the release of the bioactive peptide bradykinin, which induces inflammation, vasodilation, vessel permeability, and pain. Preclinical evidence implicates the activity of plasma kallikrein in diabetic retinopathy, which is a leading cause of visual loss in patients suffering from diabetes mellitus. Employing a technology based on phage-display combined with chemical cyclization, we have identified highly selective bicyclic peptide inhibitors with nano- and picomolar potencies toward plasma kallikrein. Stability in biological matrices was either intrinsic to the peptide or engineered via the introduction of non-natural amino acids and nonpeptidic bonds. The peptides prevented bradykinin release in vitro, and in vivo efficacy was demonstrated in both a rat paw edema model and in rodent models of diabetes-induced retinal permeability. With a highly extended half-life of ∼40 h in rabbit eyes following intravitreal administration, the bicyclic peptides are promising novel agents for the treatment of diabetic retinopathy and diabetic macular edema.


Assuntos
Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/farmacologia , Complicações do Diabetes/tratamento farmacológico , Retinopatia Diabética/tratamento farmacológico , Edema Macular/tratamento farmacológico , Edema Macular/etiologia , Calicreína Plasmática/antagonistas & inibidores , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Animais , Bradicinina/metabolismo , Edema/tratamento farmacológico , Olho/metabolismo , Pé/patologia , Meia-Vida , Injeções Intravítreas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Permeabilidade , Inibidores de Proteases/administração & dosagem , Coelhos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Especificidade por Substrato , Corpo Vítreo/química , Corpo Vítreo/metabolismo
14.
J Med Chem ; 61(7): 2962-2972, 2018 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-29584430

RESUMO

A 26-residue peptide BimBH3 binds indiscriminately to multiple oncogenic Bcl2 proteins that regulate apoptosis of cancer cells. Specific inhibition of the BimBH3-Bcl2A1 protein-protein interaction was obtained in vitro and in cancer cells by shortening the peptide to 14 residues, inserting two cyclization constraints to stabilize a water-stable α-helix, and incorporating an N-terminal acrylamide electrophile for selective covalent bonding to Bcl2A1. Mass spectrometry of trypsin-digested bands on electrophoresis gels established covalent bonding of an electrophilic helix to just one of the three cysteines in Bcl2A1, the one (Cys55) at the BimBH3-Bcl2A1 protein-protein interaction interface. Optimizing the helix-inducing constraints and the sequence subsequently enabled electrophile removal without loss of inhibitor potency. The bicyclic helical peptides were potent, cell permeable, plasma-stable, dual inhibitors of Bcl2A1 and Mcl-1 with high selectivity over other Bcl2 proteins. One bicyclic peptide was shown to inhibit the interaction between a pro-apoptotic protein (Bim) and either endogenous Bcl2A1 or Mcl-1, to induce apoptosis of SKMel28 human melanoma cells, and to sensitize them for enhanced cell death by the anticancer drug etoposide. These approaches look promising for chemically silencing intracellular proteins.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/farmacologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Animais , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Desenho de Drogas , Sinergismo Farmacológico , Etoposídeo/farmacologia , Humanos , Melanoma/tratamento farmacológico , Antígenos de Histocompatibilidade Menor , Peptídeos/síntese química , Peptídeos/farmacologia , Ratos , Relação Estrutura-Atividade , Células U937
15.
J Am Chem Soc ; 140(6): 1998-2001, 2018 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-29400455

RESUMO

The enantioselective desymmetrization of carboxylic acids by chiral Brønsted base catalysis is reported, leading to bridged bicyclic lactones with up to 94% ee. Crystallographic analysis of a substrate-catalyst complex suggests an origin of stereocontrol, reminiscent of functional Brønsted bases in biological settings, and enabled reaction optimization. The products contain an all-carbon quaternary stereocenter and can be derivatized to functionalized cyclopentanes.


Assuntos
Compostos Bicíclicos com Pontes/síntese química , Ácidos Carboxílicos/química , Lactonas/síntese química , Biomimética , Compostos Bicíclicos com Pontes/química , Ácidos Carboxílicos/síntese química , Catálise , Cristalografia por Raios X , Ciclopentanos/síntese química , Ciclopentanos/química , Lactonas/química , Modelos Moleculares , Estereoisomerismo
16.
Molecules ; 23(2)2018 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-29419733

RESUMO

Turpentine is a volatile component of resin, which is an abundant forest resource in Southern China. As one of the most important components, the integrated application of ß-pinene has been studied. The broad-spectrum evaluation of ß-pinene and its analogues has, therefore, been necessary. In an attempt to expand the scope of agro-activity trials, the preparation and the evaluation of the herbicidal activity of a series of ß-pinene analogues against three agricultural herbs were carried out. In accordance with the overall herbicidal activity, it is noteworthy that compounds 6k, 6l, and 6m demonstrated extreme activity with IC50 values of 0.065, 0.065, and 0.052 mol active ingredients/hectare against E. crus-galli. The preliminary structure-activity relationship (SAR) was analyzed and the compounds with the appropriate volatility and substituent type that had beneficial herbicidal activity were analyzed. Simultaneously, the quantitative structure-activity relationship (QSAR) model was built and the most important structural features were indicated, which was, to a certain extent, in line with the SAR study. The study aimed to study the application of the forest resource turpentine in agriculture as a potential and alternative approach for comprehensive utilization.


Assuntos
Produção Agrícola , Terebintina/análise , Terebintina/química , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Herbicidas/química , Herbicidas/farmacologia , Modelos Moleculares , Estrutura Molecular , Monoterpenos/síntese química , Monoterpenos/química , Relação Quantitativa Estrutura-Atividade , Eletricidade Estática , Terebintina/farmacologia
17.
Bioorg Med Chem Lett ; 28(6): 1111-1115, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29426770

RESUMO

The diastereoselective synthesis and structure activity relationship (SAR) of a series of fused cyclopropyl-3-amino-2,4-oxazine (2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine)-containing BACE inhibitors is described. Through these efforts compound 2 was identified as a potent (cell IC50 = 15 nM) BACE inhibitor with acceptable ADME properties. When tested in vivo, compound 2 demonstrated a significant reduction of brain and cerebral spinal fluid (CSF) Aß40 levels (46% and 66%, respectively) in a rat pharmacodynamic study and thus represents a suitable starting point for the further development of in vivo efficacious compounds for the treatment of Alzheimer's disease.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Compostos Aza/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Inibidores Enzimáticos/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Compostos Aza/síntese química , Compostos Aza/química , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade
18.
Bioorg Med Chem ; 26(5): 1026-1034, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29422332

RESUMO

The TGFß-TGFßR signaling pathway has been reported to play a protective role in the later stages of tumorigenesis via increasing immunosuppressive Treg cells and facilitating the epithelial to mesenchymal transition (EMT). Therefore, inhibition of TGFßR has the potential to enhance antitumor immunity. Herein we disclose the identification and optimization of novel heterobicyclic inhibitors of TGFßRI that demonstrate potent inhibition of SMAD phosphorylation. Application of structure-based drug design to the novel pyrrolotriazine chemotype resulted in improved binding affinity (Ki apparent = 0.14 nM), long residence time (T1/2 > 120 min) and significantly improved potency in the PSMAD cellular assay (IC50 = 24 nM). Several analogs inhibited phosphorylation of SMAD both in vitro and in vivo. Additionally, inhibition of TGFß-stimulated phospho-SMAD was observed in primary human T cells.


Assuntos
Compostos Bicíclicos com Pontes/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Sítios de Ligação , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/farmacologia , Células Cultivadas , Cristalografia por Raios X , Desenho de Drogas , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Simulação de Dinâmica Molecular , Fosforilação , Ligação Proteica , Estrutura Terciária de Proteína , Proteínas Serina-Treonina Quinases/metabolismo , Pirróis/síntese química , Pirróis/química , Pirróis/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Proteínas Smad/metabolismo , Relação Estrutura-Atividade , Linfócitos T/citologia , Linfócitos T/metabolismo , Tiazinas/síntese química , Tiazinas/química , Tiazinas/metabolismo
19.
J Med Chem ; 61(6): 2303-2328, 2018 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-29350927

RESUMO

Multiple therapeutic opportunities have been suggested for compounds capable of selective activation of metabotropic glutamate 3 (mGlu3) receptors, but small molecule tools are lacking. As part of our ongoing efforts to identify potent, selective, and systemically bioavailable agonists for mGlu2 and mGlu3 receptor subtypes, a series of C4ß-N-linked variants of (1 S,2 S,5 R,6 S)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 1 (LY354740) were prepared and evaluated for both mGlu2 and mGlu3 receptor binding affinity and functional cellular responses. From this investigation we identified (1 S,2 S,4 S,5 R,6 S)-2-amino-4-[(3-methoxybenzoyl)amino]bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 8p (LY2794193), a molecule that demonstrates remarkable mGlu3 receptor selectivity. Crystallization of 8p with the amino terminal domain of hmGlu3 revealed critical binding interactions for this ligand with residues adjacent to the glutamate binding site, while pharmacokinetic assessment of 8p combined with its effect in an mGlu2 receptor-dependent behavioral model provides estimates for doses of this compound that would be expected to selectively engage and activate central mGlu3 receptors in vivo.


Assuntos
Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/farmacologia , Agonistas de Aminoácidos Excitatórios/síntese química , Agonistas de Aminoácidos Excitatórios/farmacologia , Receptores de Glutamato Metabotrópico/agonistas , Animais , Compostos Bicíclicos com Pontes/farmacocinética , Cristalografia por Raios X , AMP Cíclico/farmacologia , Agonistas de Aminoácidos Excitatórios/farmacocinética , Antagonistas de Aminoácidos Excitatórios/farmacologia , Humanos , Masculino , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fenciclidina/antagonistas & inibidores , Fenciclidina/farmacologia , Ligação Proteica , Ratos , Ratos Sprague-Dawley
20.
Bioorg Med Chem Lett ; 28(2): 85-93, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29233651

RESUMO

We disclose the optimization of a high throughput screening hit to yield benzothiazine and tetrahydroquinoline sulfonamides as potent RORγt inverse agonists. However, a majority of these compounds showed potent activity against pregnane X receptor (PXR) and modest activity against liver X receptor α (LXRα). Structure-based drug design (SBDD) led to the identification of benzothiazine and tetrahydroquinoline sulfonamide analogs which completely dialed out LXRα activity and were less potent at PXR. Pharmacodynamic (PD) data for compound 35 in an IL-23 induced IL-17 mouse model is discussed along with the implications of a high Ymax in the PXR assay for long term preclinical pharmacokinetic (PK) studies.


Assuntos
Compostos Bicíclicos com Pontes/farmacologia , Desenho de Drogas , Propanóis/farmacologia , Receptores do Ácido Retinoico/agonistas , Receptores de Esteroides/agonistas , Sulfonamidas/farmacologia , Animais , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Receptores X do Fígado/agonistas , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Estrutura Molecular , Receptor de Pregnano X , Propanóis/síntese química , Propanóis/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
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