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1.
J Neurosci ; 34(35): 11621-30, 2014 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-25164658

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/patologia
2.
Acta Crystallogr D Biol Crystallogr ; 69(Pt 6): 1124-37, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23695257

RESUMO

The aspartic protease BACE2 is responsible for the shedding of the transmembrane protein Tmem27 from the surface of pancreatic ß-cells, which leads to inactivation of the ß-cell proliferating activity of Tmem27. This role of BACE2 in the control of ß-cell maintenance suggests BACE2 as a drug target for diabetes. Inhibition of BACE2 has recently been shown to lead to improved control of glucose homeostasis and to increased insulin levels in insulin-resistant mice. BACE2 has 52% sequence identity to the well studied Alzheimer's disease target enzyme ß-secretase (BACE1). High-resolution BACE2 structures would contribute significantly to the investigation of this enzyme as either a drug target or anti-target. Surface mutagenesis, BACE2-binding antibody Fab fragments, single-domain camelid antibody VHH fragments (Xaperones) and Fyn-kinase-derived SH3 domains (Fynomers) were used as crystallization helpers to obtain the first high-resolution structures of BACE2. Eight crystal structures in six different packing environments define an ensemble of low-energy conformations available to the enzyme. Here, the different strategies used for raising and selecting BACE2 binders for cocrystallization are described and the crystallization success, crystal quality and the time and resources needed to obtain suitable crystals are compared.


Assuntos
Secretases da Proteína Precursora do Amiloide/química , Ácido Aspártico Endopeptidases/química , Fragmentos Fab das Imunoglobulinas/química , Células Secretoras de Insulina/enzimologia , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Área Sob a Curva , Ácido Aspártico Endopeptidases/genética , Ácido Aspártico Endopeptidases/metabolismo , Domínio Catalítico , Cristalização , Humanos , Fragmentos Fab das Imunoglobulinas/metabolismo , Células Secretoras de Insulina/metabolismo , Camundongos , Modelos Moleculares , Mutagênese , Conformação Proteica , Ressonância de Plasmônio de Superfície , Difração de Raios X
3.
Bioorg Med Chem Lett ; 23(14): 4239-43, 2013 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-23735744

RESUMO

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-Atividade
4.
Bioorg Med Chem Lett ; 20(17): 5313-9, 2010 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-20650636

RESUMO

A series of (3R,4R)-pyrrolidine-3,4-dicarboxylic acid amides was investigated with respect to their factor Xa inhibitory activity, selectivity, pharmacokinetic properties, and ex vivo antithrombotic activity. The clinical candidate from this series, R1663, exhibits excellent selectivity against a panel of serine proteases and good pharmacokinetic properties in rats and monkeys. A Phase I clinical study with R1663 has been finalized.


Assuntos
Inibidores do Fator Xa , Pirrolidinas/farmacologia , Pirrolidinas/química
5.
Bioorg Med Chem Lett ; 19(9): 2468-73, 2009 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-19349176

RESUMO

Design, synthesis, and SAR of novel alpha-alkoxy-beta-arylpropionic acids as potent and balanced PPARalphagamma coagonists are described. One representative thereof, Aleglitazar ((S)-2Aa), was chosen for clinical development. Its X-ray structure in complex with both receptors as well as its high efficacy in animal models of T2D and dyslipidemia are also presented.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Oxazóis/síntese química , Oxazóis/farmacologia , PPAR alfa/agonistas , PPAR gama/agonistas , Tiofenos/síntese química , Tiofenos/farmacologia , Animais , Química Farmacêutica/métodos , Cristalografia por Raios X/métodos , Desenho de Fármacos , Dislipidemias/tratamento farmacológico , Humanos , Concentração Inibidora 50 , Ligantes , Modelos Químicos , Estrutura Molecular , Receptores Citoplasmáticos e Nucleares/metabolismo
6.
Nat Cell Biol ; 18(3): 328-36, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26900752

RESUMO

Activation of brown adipose tissue (BAT) controls energy homeostasis in rodents and humans and has emerged as an innovative strategy for the treatment of obesity and type 2 diabetes mellitus. Here we show that ageing- and obesity-associated dysfunction of brown fat coincides with global microRNA downregulation due to reduced expression of the microRNA-processing node Dicer1. Consequently, heterozygosity of Dicer1 in BAT aggravated diet-induced-obesity (DIO)-evoked deterioration of glucose metabolism. Analyses of differential microRNA expression during preadipocyte commitment and mouse models of progeria, longevity and DIO identified miR-328 as a regulator of BAT differentiation. Reducing miR-328 blocked preadipocyte commitment, whereas miR-328 overexpression instigated BAT differentiation and impaired muscle progenitor commitment-partly through silencing of the ß-secretase Bace1. Loss of Bace1 enhanced brown preadipocyte specification in vitro and was overexpressed in BAT of obese and progeroid mice. In vivo Bace1 inhibition delayed DIO-induced weight gain and improved glucose tolerance and insulin sensitivity. These experiments reveal Dicer1-miR-328-Bace1 signalling as a determinant of BAT function, and highlight the potential of Bace1 inhibition as a therapeutic approach to improve not only neurodegenerative diseases but also ageing- and obesity-associated impairments of BAT function.


Assuntos
Tecido Adiposo Marrom/metabolismo , Secretases da Proteína Precursora do Amiloide/genética , Ácido Aspártico Endopeptidases/genética , Diferenciação Celular/fisiologia , RNA Helicases DEAD-box/genética , MicroRNAs/genética , Ribonuclease III/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , RNA Helicases DEAD-box/metabolismo , Metabolismo Energético/fisiologia , Homeostase/fisiologia , Resistência à Insulina/fisiologia , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Obesidade/genética , Obesidade/metabolismo , Ribonuclease III/metabolismo
7.
J Med Chem ; 56(23): 9789-801, 2013 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-24224654

RESUMO

Starting from the weakly active dual CatS/K inhibitor 5, structure-based design supported by X-ray analysis led to the discovery of the potent and selective (>50,000-fold vs CatK) cyclopentane derivative 22 by exploiting specific ligand-receptor interactions in the S2 pocket of CatS. Changing the central cyclopentane scaffold to the analogous pyrrolidine derivative 57 decreased the enzyme as well as the cell-based activity significantly by 24- and 69-fold, respectively. The most promising scaffold identified was the readily accessible proline derivative (e.g., 79). This compound, with an appealing ligand efficiency (LE) of 0.47, included additional structural modifications binding in the S1 and S3 pockets of CatS, leading to favorable in vitro and in vivo properties. Compound 79 reduced IL-2 production in a transgenic DO10.11 mouse model of antigen presentation in a dose-dependent manner with an ED50 of 5 mg/kg.


Assuntos
Catepsinas/antagonistas & inibidores , Inibidores de Cisteína Proteinase/síntese química , Animais , Ciclopentanos/química , Inibidores de Cisteína Proteinase/farmacocinética , Humanos , Camundongos , Prolina/análogos & derivados , Relação Estrutura-Atividade
8.
J Med Chem ; 56(10): 3980-95, 2013 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-23590342

RESUMO

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 X
9.
Cardiovasc Res ; 89(1): 244-52, 2011 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-20693162

RESUMO

AIMS: mast cells have been shown to accumulate in the adventitia of human atherosclerotic plaques and were recently demonstrated by us to contribute to plaque progression and instability. In this study, we investigated whether selective inhibition of mast cell chymases would affect the lesion development and stability. METHODS AND RESULTS: the protease inhibitor RO5066852 appeared to be a potent inhibitor of chymase activity in vitro and ex vivo. With this inhibitor, we provide three lines of evidence that chymase inhibition can prevent many pro-atherogenic activities. First, oral administration of RO5066852 reduced spontaneous atherosclerosis in the thoracic aorta of apoE(-/-) mice. Second, chymase inhibition prevented the accelerated plaque progression observed in apoE(-/-) mice that were exposed to repetitive episodes of systemic mast cell activation. Furthermore, RO5066852 enhanced lesional collagen content and reduced necrotic core size. Third, RO5066852 treatment almost completely normalized the increased frequency and size of intraplaque haemorrhages observed in apoE(-/-) mice after acute perivascular mast cell activation in advanced atherosclerosis. CONCLUSION: our data indicate that chymase inhibition can inhibit pro-atherogenic and plaque destabilizing effects which are associated with perivascular mast cell activation. Our study thus identifies pharmacological chymase inhibition as a potential therapeutic modality for atherosclerotic plaque stabilization.


Assuntos
Apolipoproteínas E/deficiência , Quimases/antagonistas & inibidores , Ácidos Indolacéticos/farmacologia , Mastócitos/efeitos dos fármacos , Mastócitos/enzimologia , Naftalenos/farmacologia , Placa Aterosclerótica/prevenção & controle , Animais , Apolipoproteínas E/genética , Quimases/genética , Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Placa Aterosclerótica/tratamento farmacológico , Placa Aterosclerótica/enzimologia , Placa Aterosclerótica/patologia , Inibidores de Proteases/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de LDL/deficiência , Receptores de LDL/genética
10.
Cell Metab ; 14(3): 365-77, 2011 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-21907142

RESUMO

Decreased ß cell mass and function are hallmarks of type 2 diabetes. Here we identified, through a siRNA screen, beta site amyloid precursor protein cleaving enzyme 2 (Bace2) as the sheddase of the proproliferative plasma membrane protein Tmem27 in murine and human ß cells. Mice with functionally inactive Bace2 and insulin-resistant mice treated with a newly identified Bace2 inhibitor both display augmented ß cell mass and improved control of glucose homeostasis due to increased insulin levels. These results implicate Bace2 in the control of ß cell maintenance and provide a rational strategy to inhibit this protease for the expansion of functional pancreatic ß cell mass.


Assuntos
Secretases da Proteína Precursora do Amiloide , Ácido Aspártico Endopeptidases , Diabetes Mellitus Tipo 2/metabolismo , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Glicoproteínas de Membrana/metabolismo , Transdução de Sinais/genética , Adolescente , Sequência de Aminoácidos , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/genética , Ácido Aspártico Endopeptidases/metabolismo , Glicemia/análise , Células Cultivadas , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Inibidores Enzimáticos/farmacologia , Feminino , Inativação Gênica/efeitos dos fármacos , Humanos , Insulina/farmacologia , Resistência à Insulina , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/efeitos dos fármacos , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Dados de Sequência Molecular , Plasmídeos , RNA Interferente Pequeno/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Especificidade da Espécie , Especificidade por Substrato , Transfecção
11.
ChemMedChem ; 4(6): 951-6, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19326383

RESUMO

An X-ray-guided design approach led to the identification of a novel, balanced class of alpha-ethoxy-phenylpropionic acid-derived dual PPARalpha/gamma agonists. The series shows a wide range of PPARalpha/gamma ratios within a rather narrow structural space. Advanced compounds possess favorable physicochemical and pharmacokinetic profiles and show a high efficacy in T2D and dyslipidemia animal models.


Assuntos
Hipolipemiantes/química , PPAR alfa/agonistas , PPAR gama/agonistas , Fenilpropionatos/química , Animais , Simulação por Computador , Cristalografia por Raios X , Diabetes Mellitus Tipo 2/tratamento farmacológico , Desenho de Fármacos , Humanos , Hipolipemiantes/síntese química , Hipolipemiantes/farmacocinética , Camundongos , PPAR alfa/metabolismo , PPAR gama/metabolismo , Fenilpropionatos/síntese química , Fenilpropionatos/farmacocinética , Ratos , Estereoisomerismo , Relação Estrutura-Atividade
12.
J Org Chem ; 71(5): 2000-8, 2006 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-16496986

RESUMO

A new efficient synthesis of two novel classes of NK1 receptor antagonists, among them befetupitant and netupitant, starting from 6-chloronicotinic acid is described. The introduction of the o-tolyl substituent at C4 of the pyridine ring was achieved by a one-pot selective 1,4-Grignard addition/oxidation sequence to 6-chloronicotinic acid or a derivative of it. The scope of this addition/oxidation sequence was examined. It was also shown that the carboxylic function can be converted to a methyl amino group by a Hofmann rearrangement followed by reduction. Furthermore, a new high-yielding synthesis of 2-(3,5-bistrifluoromethylphenyl)-2-methyl propionic acid based on the carbonylation of the tertiary alcohol obtained by Grignard addition of 3,5-bis(trifluoromethyl)bromobenzene to acetone was established.


Assuntos
Antagonistas dos Receptores de Neurocinina-1 , Ácidos Nicotínicos/química , Propionatos/química , Piridinas/síntese química , Animais , Humanos , Propionatos/síntese química , Piridinas/farmacologia
13.
Bioorg Med Chem Lett ; 16(15): 4016-20, 2006 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-16737814

RESUMO

In the quest for novel PPARalpha/gamma co-agonists as putative drugs for the treatment of type 2 diabetes and dyslipidemia, we have used a structure-based design approach to identify propionic acids with a 1,5-disubstituted indole scaffold as potent PPARalpha/gamma activators. Compounds 13, 24, and 28 are examples of submicromolar dual agonists with different alpha/gamma EC50 ratios that are selective against the delta-isoform. Analysis of the X-ray complex structure of PPARgamma with the indole propionic acid 13 provides a rationalization for some of the observed SAR.


Assuntos
Indóis/química , Indóis/farmacologia , PPAR alfa/agonistas , PPAR gama/agonistas , Desenho de Fármacos , Estrutura Molecular , Relação Estrutura-Atividade , Difração de Raios X
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