RESUMO
Therapeutic approaches for prevention or reduction of amyloidosis are currently a main objective in basic and clinical research on Alzheimer's disease. Among the agents explored in clinical trials are anti-Aß peptide antibodies and secretase inhibitors. Most anti-Aß antibodies are considered to act via inhibition of amyloidosis and enhanced clearance of existing amyloid, although secretase inhibitors reduce the de novo production of Aß. Limited information is currently available on the efficacy and potential advantages of combinatorial antiamyloid treatment. We performed a chronic study in APPLondon transgenic mice that received treatment with anti-Aß antibody gantenerumab and BACE inhibitor RO5508887, either as mono- or combination treatment. Treatment aimed to evaluate efficacy on amyloid progression, similar to preexisting amyloidosis as present in Alzheimer's disease patients. Mono-treatments with either compound caused a dose-dependent reduction of total brain Aß and amyloid burden. Combination treatment with both compounds significantly enhanced the antiamyloid effect. The observed combination effect was most pronounced for lowering of amyloid plaque load and plaque number, which suggests effective inhibition of de novo plaque formation. Moreover, significantly enhanced clearance of pre-existing amyloid plaques was observed when gantenerumab was coadministered with RO5508887. BACE inhibition led to a significant time- and dose-dependent decrease in CSF Aß, which was not observed for gantenerumab treatment. Our results demonstrate that combining these two antiamyloid agents enhances overall efficacy and suggests that combination treatments may be of clinical relevance.
Assuntos
Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Anticorpos Monoclonais/administração & dosagem , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Encéfalo/efeitos dos fármacos , Inibidores Enzimáticos/administração & dosagem , Peptídeos beta-Amiloides/antagonistas & inibidores , Animais , Anticorpos Monoclonais Humanizados , Encéfalo/patologia , Modelos Animais de Doenças , Quimioterapia Combinada , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Placa Amiloide/patologiaRESUMO
A series of amides bearing a variety of amidine head groups was investigated as BACE1 inhibitors with respect to inhibitory activity in a BACE1 enzyme as well as a cell-based assay. Determination of their basicity as well as their properties as substrates of P-glycoprotein revealed that a 2-amino-1,3-oxazine head group would be a suitable starting point for further development of brain penetrating compounds for potential Alzheimer's disease treatment.
Assuntos
Amidas/química , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Inibidores de Proteases/química , Doença de Alzheimer/tratamento farmacológico , Amidas/metabolismo , Amidas/uso terapêutico , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Sítios de Ligação , Humanos , Simulação de Acoplamento Molecular , Inibidores de Proteases/metabolismo , Inibidores de Proteases/uso terapêutico , Ligação Proteica , Estrutura Terciária de Proteína , Relação Estrutura-AtividadeRESUMO
An extensive fluorine scan of 1,3-oxazines revealed the power of fluorine(s) to lower the pKa and thereby dramatically change the pharmacological profile of this class of BACE1 inhibitors. The CF3 substituted oxazine 89, a potent and highly brain penetrant BACE1 inhibitor, was able to reduce significantly CSF Aß40 and 42 in rats at oral doses as low as 1 mg/kg. The effect was long lasting, showing a significant reduction of Aß40 and 42 even after 24 h. In contrast to 89, compound 1b lacking the CF3 group was virtually inactive in vivo.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Animais , Química Encefálica , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Feminino , Flúor/química , Humanos , Indicadores e Reagentes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Moleculares , Oxazinas/síntese química , Oxazinas/farmacologia , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Difração de Raios XRESUMO
G protein-coupled receptors (GPCRs) share a common architecture consisting of seven transmembrane (TM) domains. Various lines of evidence suggest that this fold provides a generic binding pocket within the TM region for hosting agonists, antagonists, and allosteric modulators. Hence, an automated method was developed that allows a fast analysis and comparison of these generic ligand binding pockets across the entire GPCR family by providing the relevant information for all GPCRs in the same format. This methodology compiles amino acids lining the TM binding pocket including parts of the ECL2 loop in a so-called 1D ligand binding pocket vector and translates these 1D vectors in a second step into 3D receptor pharmacophore models. It aims to support various aspects of GPCR drug discovery in the pharmaceutical industry. Applications of pharmacophore similarity analysis of these 1D LPVs include definition of receptor subfamilies, prediction of species differences within subfamilies in regard to in vitro pharmacology and identification of nearest neighbors for GPCRs of interest to generate starting points for GPCR lead identification programs. These aspects of GPCR research are exemplified in the field of melanopsins, trace amine-associated receptors and somatostatin receptor subtype 5. In addition, it is demonstrated how 3D pharmacophore models of the LPVs can support the prediction of amino acids involved in ligand recognition, the understanding of mutational data in a 3D context and the elucidation of binding modes for GPCR ligands and their evaluation. Furthermore, guidance through 3D receptor pharmacophore modeling for the synthesis of subtype-specific GPCR ligands will be reported. Illustrative examples are taken from the GPCR family class C, metabotropic glutamate receptors 1 and 5 and sweet taste receptors, and from the GPCR class A, e.g. nicotinic acid and 5-hydroxytryptamine 5A receptor.
Assuntos
Descoberta de Drogas/métodos , Receptores Acoplados a Proteínas G/química , Sequência de Aminoácidos , Sítios de Ligação , Humanos , Ligantes , Modelos Moleculares , Dados de Sequência Molecular , Conformação Proteica , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/metabolismoRESUMO
Benzoylisoindolines were discovered as a novel structural class of GlyT1 inhibitors. SAR studies and subsequent lead optimization efforts focused primarily on addressing hERG liability and on improving in vivo efficacy resulted in the identification of potent GlyT1 inhibitors displaying excellent selectivity and in vivo PD and PK profiles.
Assuntos
Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Animais , Permeabilidade da Membrana Celular , Descoberta de Drogas , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Glicina/análise , Humanos , Isoindóis/química , Isoindóis/farmacocinética , Isoindóis/farmacologia , Camundongos , Ratos , Solubilidade , Relação Estrutura-AtividadeRESUMO
Pyrido pyrimidinones are selective agonists of the human high affinity niacin receptor GPR109A (HM74A). They show no activity on the highly homologous low affinity receptor GPR109B (HM74). Starting from a high throughput screening hit the in vitro activity of the pyrido pyrimidinones was significantly improved providing lead compounds suitable for further optimization.
Assuntos
Niacina/metabolismo , Pirimidinonas/química , Pirimidinonas/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Receptores Nicotínicos/metabolismo , Animais , Microssomos Hepáticos/metabolismo , Pirimidinonas/administração & dosagem , Pirimidinonas/metabolismo , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
The GlyT1 transporter has emerged as a key novel target for the treatment of schizophrenia. Herein, we report on the optimization of the 2-alkoxy-5-methylsulfonebenzoylpiperazine class of GlyT1 inhibitors to improve hERG channel selectivity and brain penetration. This effort culminated in the discovery of compound 10a (RG1678), the first potent and selective GlyT1 inhibitor to have a beneficial effect in schizophrenic patients in a phase II clinical trial.
Assuntos
Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Piperazinas/síntese química , Psicotrópicos/síntese química , Esquizofrenia/tratamento farmacológico , Sulfonas/síntese química , Animais , Encéfalo/metabolismo , Células CHO , Cricetinae , Cricetulus , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Humanos , Macaca fascicularis , Masculino , Camundongos , Microdiálise , Atividade Motora/efeitos dos fármacos , Técnicas de Patch-Clamp , Piperazinas/farmacocinética , Piperazinas/farmacologia , Psicotrópicos/farmacocinética , Psicotrópicos/farmacologia , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonas/farmacocinética , Sulfonas/farmacologiaRESUMO
Design, synthesis, and SAR are described for a class of DPP-IV inhibitors based on aminobenzo[a]quinolizines with non-aromatic substituents in the S1 specificity pocket. One representative thereof, carmegliptin (8p), was chosen for clinical development. Its X-ray structure in complex with the enzyme and early efficacy data in animal models of type 2 diabetes are also presented.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV , Inibidores da Dipeptidil Peptidase IV/síntese química , Desenho de Fármacos , Hipoglicemiantes/síntese química , Quinolizinas/síntese química , Animais , Ensaios Clínicos Fase II como Assunto , Cristalografia por Raios X , Preparações de Ação Retardada , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/metabolismo , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Cães , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/uso terapêutico , Macaca fascicularis , Camundongos , Quinolizinas/administração & dosagem , Quinolizinas/uso terapêutico , Ratos , Ratos Wistar , Ratos ZuckerRESUMO
Synthesis and SAR are described for a structurally distinct class of DPP-IV inhibitors based on aminobenzo[a]quinolizines bearing (hetero-)aromatic substituents in the S1 specificity pocket. The m-(fluoromethyl)-phenyl derivative (S,S,S)-2g possesses the best fit in the S1 pocket. However, (S,S,S)-2i, bearing a more hydrophilic 5-methyl-pyridin-2-yl residue as substituent for the S1 pocket, displays excellent in vivo activity and superior drug-like properties.
Assuntos
Inibidores da Dipeptidil Peptidase IV , Inibidores da Dipeptidil Peptidase IV/química , Quinolizinas/química , Animais , Cristalografia por Raios X , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Humanos , Inibidores de Proteases/química , Inibidores de Proteases/metabolismo , Inibidores de Proteases/farmacologia , Quinolizinas/metabolismo , Quinolizinas/farmacologia , Ratos , Ratos ZuckerRESUMO
Several novel classes of potent and small amide-type inhibitors of glycine transport (GlyT1) were developed through sequential simplification of a benzodiazepinone-lead structure identified from a high-throughput screening. The most potent compounds of these structurally simple classes show low nanomolar inhibition at the GlyT1 target.
Assuntos
Amidas/química , Química Farmacêutica/métodos , Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Glicina/química , Animais , Benzodiazepinonas/química , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Camundongos , Microssomos/química , Modelos Químicos , Permeabilidade , Solubilidade , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Screening of the Roche compound library led to the identification of the benzoylpiperazine 7 as a structurally novel GlyT1 inhibitor. The SAR which was developed in this series resulted in the discovery of highly potent compounds displaying excellent selectivity against the GlyT2 isoform, drug-like properties, and in vivo efficacy after oral administration.
Assuntos
Benzoatos/química , Benzoatos/farmacologia , Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Piperazinas/química , Piperazinas/farmacologia , Administração Oral , Encéfalo/efeitos dos fármacos , Técnicas de Química Combinatória , Desenho de Fármacos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The application of the evolutionary fragment-based de novo design tool TOPology Assigning System (TOPAS), starting from a known CB1R (CB-1 receptor) ligand, followed by further refinement principles, including pharmacophore compliance, chemical tractability, and drug likeness, allowed the identification of benzodioxoles as a novel CB1R inverse agonist series. Extensive multidimensional optimization was rewarded by the identification of promising lead compounds, showing in vivo activity. These compounds reversed the CP-55940-induced hypothermia in Naval Medical Research Institute (NMRI) mice and reduced body-weight gain, as well as fat mass, in diet-induced obese Sprague-Dawley rats. Herein, we disclose the tools and strategies that were employed for rapid hit identification, synthesis and generation of structure-activity relationships, ultimately leading to the identification of (+)-[( R)-2-(2,4-dichloride-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone ( R)-14g . Biochemical, pharmacokinetic, and pharmacodynamic characteristics of ( R)-14g are discussed.
Assuntos
Fármacos Antiobesidade/administração & dosagem , Fármacos Antiobesidade/farmacologia , Benzodioxóis/administração & dosagem , Benzodioxóis/farmacologia , Obesidade/tratamento farmacológico , Receptor CB1 de Canabinoide/agonistas , Animais , Fármacos Antiobesidade/química , Benzodioxóis/síntese química , Benzodioxóis/química , Peso Corporal/efeitos dos fármacos , Cristalografia por Raios X , Cicloexanóis/antagonistas & inibidores , Cicloexanóis/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Hipotermia/induzido quimicamente , Ligantes , Masculino , Camundongos , Microssomos/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/química , Relação Estrutura-AtividadeRESUMO
In a search for novel DPP-IV inhibitors, 2-aminobenzo[a]quinolizines were identified as submicromolar HTS hits. Due to the difficult synthetic access to this compound class, 1,3-disubstituted 4-aminopiperidines were used as model compounds for optimization. The developed synthetic methodology and the SAR could be transferred to the 2-aminobenzo[a]quinolizine series, leading to highly active DPP-IV inhibitors.
Assuntos
Inibidores de Adenosina Desaminase , Inibidores da Dipeptidil Peptidase IV , Glicoproteínas/antagonistas & inibidores , Piperidinas/química , Inibidores de Proteases/química , Adenosina Desaminase/química , Dipeptidil Peptidase 4/química , Glicoproteínas/química , Humanos , Piperidinas/síntese química , Piperidinas/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Conformação Proteica , Relação Estrutura-AtividadeRESUMO
The desymmetrisation of centrosymmetric molecules by enantioselective carbon-carbon bond formation has been reported for the first time. A bimetallic zinc catalyst developed by Trost was exploited in the desymmetrisation of a centrosymmetric dialdehyde. The approach was successful with a range of ketone nucleophiles and was uniformly highly diastereoselective (>98:<2). The yield and the enantioselectivity of the reaction varied as a function of the ketone used, and the desymmetrised products were obtained in up to 74 % yield and 97 % ee (ee=enantiomeric excess). The desymmetrisation of centrosymmetric molecules by enantioselective carbon-carbon bond formation is an efficient and convergent synthetic approach which is likely to find wide application in synthesis, particularly in the total synthesis of natural products with embedded centrosymmetric fragments.
Assuntos
Aldeídos/química , Carbono/química , Catálise , Conformação Molecular , Estrutura Molecular , Estereoisomerismo , Zinco/químicaRESUMO
We have previously identified the 7,8,9,10-tetrahydro-7,10-ethano-1,2,4-triazolo[3,4-a]phthalazine (1) as a potent partial agonist for the alpha(3) receptor subtype with 5-fold selectivity in binding affinity over alpha(1). This paper describes a detailed investigation of the substituents on this core structure at both the 3- and 6-positions. Despite evaluating a wide range of groups, the maximum selectivity that could be achieved in terms of affinity for the alpha(3) subtype over the alpha(1) subtype was 12-fold (for 57). Although most analogues showed no selectivity in terms of efficacy, some did show partial agonism at alpha(1) and antagonism at alpha(3) (e.g., 25 and 75). However, two analogues tested (93 and 96), both with triazole substituents in the 6-position, showed significantly higher efficacy for the alpha(3) subtype over the alpha(1) subtype. This was the first indication that selectivity in efficacy in the required direction could be achieved in this series.
Assuntos
Agonistas de Receptores de GABA-A , Ftalazinas/síntese química , Triazóis/síntese química , Animais , Sítios de Ligação , Linhagem Celular , Feminino , Humanos , Modelos Moleculares , Oócitos/efeitos dos fármacos , Oócitos/fisiologia , Técnicas de Patch-Clamp , Ftalazinas/química , Ftalazinas/farmacologia , Subunidades Proteicas/agonistas , Subunidades Proteicas/fisiologia , Ensaio Radioligante , Receptores de GABA-A/fisiologia , Relação Estrutura-Atividade , Triazóis/química , Triazóis/farmacologia , Xenopus laevisRESUMO
2,5-Dihydropyrazolo[4,3-c]pyridin-3-ones are GABAA receptor benzodiazepine binding site ligands with functional selectivity for the alpha3 subtype over the alpha1 subtype. SAR studies to optimise this functional selectivity are described.