RESUMO
Catalytic oxidative cyclisation reactions have been employed for the synthesis of the E and F rings of the complex natural product target pectenotoxinâ 4. The choice of metal catalyst (cobalt- or osmium-based) allowed for the formation of THF rings with either trans or cis stereoselectivity. Fragment union using a modified Julia reaction then enabled the synthesis of an advanced synthetic intermediate containing the EF and G rings of the target.
RESUMO
Dual-specificity tyrosine-regulated kinase 1A (DYRK1A) regulates the proliferation and differentiation of neuronal progenitor cells during brain development. Consequently, DYRK1A has attracted interest as a target for the treatment of neurodegenerative diseases, including Alzheimer's disease (AD) and Down's syndrome. Recently, the inhibition of DYRK1A has been investigated as a potential treatment for diabetes, while DYRK1A's role as a mediator in the cell cycle has garnered interest in oncologic indications. Structure-activity relationship (SAR) analysis in combination with high-resolution X-ray crystallography leads to a series of pyrazolo[1,5-b]pyridazine inhibitors with excellent ligand efficiencies, good physicochemical properties, and a high degree of selectivity over the kinome. Compound 11 exhibited good permeability and cellular activity without P-glycoprotein liability, extending the utility of 11 in an in vivo setting. These pyrazolo[1,5-b]pyridazines are a viable lead series in the discovery of new therapies for the treatment of diseases linked to DYRK1A function.
Assuntos
Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Ligantes , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Solubilidade , Relação Estrutura-Atividade , Quinases DyrkRESUMO
A series of analogues of the pyrazole lead 1 were synthesized in which the heterocyclic core was replaced with an imidazole. A number of potent antagonists were identified and structure-activity relationships (SAR) were investigated both with respect to activity at the P2X(7) receptor and in vitro metabolic stability. Compound 10 was identified as a potent P2X(7) antagonist with reduced in vitro metabolism and high solubility.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Imidazóis/química , Antagonistas do Receptor Purinérgico P2 , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Humanos , Imidazóis/síntese química , Imidazóis/farmacologia , Pirazóis/química , Ratos , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2X7 , Relação Estrutura-AtividadeRESUMO
High-throughput screening identified compound 1 as a potent P2X(7) receptor antagonist suitable for lead optimisation. Structure-activity relationships (SAR) of a series of (1H-pyrazol-4-yl)acetamides were investigated and compound 32 was identified as a potent P2X(7) antagonist with enhanced potency and favourable physicochemical and pharmacokinetic properties.
Assuntos
Acetamidas/química , Anti-Infecciosos/síntese química , Antagonistas do Receptor Purinérgico P2 , Pirazóis/síntese química , Acetamidas/síntese química , Acetamidas/farmacocinética , Administração Oral , Animais , Anti-Infecciosos/química , Anti-Infecciosos/farmacocinética , Ensaios de Triagem em Larga Escala , Humanos , Injeções Intravenosas , Pirazóis/química , Pirazóis/farmacocinética , Ratos , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2X7 , Relação Estrutura-AtividadeRESUMO
Structure-activity relationships (SAR) of analogues of lead compound 1 were investigated and compound 16 was selected for further study in animal models of pain. Compound 16 was shown to be a potent antihyperalgesic agent in both the rat acute complete Freund's adjuvant (CFA) model of inflammatory pain [Iadarola, M. J.; Douglass, J.; Civelli, O.; Naranjo, J. R. rain Res.1988, 455, 205] and the knee joint model of chronic inflammatory pain [Wilson, A. W.; Medhurst, S. J.; Dixon, C. I.; Bontoft, N. C.; Winyard, L. A.; Brackenborough, K. T.; De Alba, J.; Clarke, C. J.; Gunthorpe, M. J.; Hicks, G. A.; Bountra, C.; McQueen, D. S.; Chessell, I. P. Eur. J. Pain2006, 10, 537].
Assuntos
Acetamidas/química , Antagonistas do Receptor Purinérgico P2X , Pirazóis/química , Acetamidas/síntese química , Acetamidas/uso terapêutico , Administração Oral , Animais , Modelos Animais de Doenças , Humanos , Dor/tratamento farmacológico , Pirazóis/síntese química , Ratos , Receptores Purinérgicos P2X7/metabolismo , Relação Estrutura-AtividadeRESUMO
A backup molecule to compound 2 was sought by targeting the most likely metabolically vulnerable site in this molecule. Compound 18 was subsequently identified as a potent P2X(7) antagonist with very low in vivo clearance and high oral bioavailability in all species examined. Some evidence to support the role of P2X(7) in the etiology of pain is also presented.
Assuntos
Imidazolinas/farmacologia , Antagonistas Purinérgicos/farmacologia , Receptores Purinérgicos P2X7/efeitos dos fármacos , Administração Oral , Animais , Disponibilidade Biológica , Meia-Vida , Haplorrinos , Imidazolinas/administração & dosagem , Imidazolinas/química , Imidazolinas/farmacocinética , Antagonistas Purinérgicos/administração & dosagem , Antagonistas Purinérgicos/química , Antagonistas Purinérgicos/farmacocinética , RatosRESUMO
Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer's disease. Herein, is described a series of potent inhibitors based on an hydroxyethylamine (HEA) transition state mimetic template. These inhibitors interact with the non prime side of the enzyme using a novel edge-to-face interaction with Arg-296.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Arginina/química , Etilaminas/química , Inibidores de Proteases/química , Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/química , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Sítios de Ligação , Simulação por Computador , Cristalografia por Raios X , Etilaminas/síntese química , Etilaminas/uso terapêutico , Inibidores de Proteases/síntese química , Inibidores de Proteases/uso terapêutico , Ratos , Relação Estrutura-AtividadeRESUMO
A computational lead-hopping exercise identified compound 4 as a structurally distinct P2X(7) receptor antagonist. Structure-activity relationships (SAR) of a series of pyroglutamic acid amide analogues of 4 were investigated and compound 31 was identified as a potent P2X(7) antagonist with excellent in vivo activity in animal models of pain, and a profile suitable for progression to clinical studies.
Assuntos
Amidas/farmacologia , Antagonistas do Receptor Purinérgico P2/farmacologia , Ácido Pirrolidonocarboxílico/química , Receptores Purinérgicos P2X7/efeitos dos fármacos , Amidas/química , Descoberta de Drogas , Modelos Moleculares , Antagonistas do Receptor Purinérgico P2/química , Relação Estrutura-AtividadeRESUMO
Replacing trifluoroacetic acid with a catalytic amount of Lewis acid in the osmium mediated oxidative cyclization results in higher yielding reactions that can proceed nearly an order of magnitude faster. The osmium loading can also be reduced to as little as 0.2 mol %. Furthermore, these mildly acidic conditions are capable of tolerating a wide range of acid sensitive protecting groups that are incompatible with previous cyclization conditions.
Assuntos
Ácidos/química , Ciclização , Osmio/química , OxirreduçãoRESUMO
Our first generation of hydroxyethylamine BACE-1 inhibitors proved unlikely to provide molecules that would lower amyloid in an animal model at low oral doses. This observation led us to the discovery of a second generation of inhibitors having nanomolar activity in a cell-based assay and with the potential for improved pharmacokinetic profiles. In this Letter, we describe our successful strategy for the optimization of oral bioavailability and also give insights into the design of compounds with the potential for improved brain penetration.
Assuntos
Ácido Aspártico Endopeptidases/antagonistas & inibidores , Etilaminas/química , Inibidores de Proteases/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Disponibilidade Biológica , Cães , Etilaminas/síntese química , Etilaminas/farmacocinética , Camundongos , Camundongos Knockout , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
Our first generation of hydroxyethylamine transition-state mimetic BACE-1 inhibitors allowed us to validate BACE-1 as a key target for Alzheimer's disease by demonstrating amyloid lowering in an animal model, albeit at rather high doses. Finding a molecule from this series which was active at lower oral doses proved elusive and demonstrated the need to find a novel series of inhibitors with improved pharmacokinetics. This Letter describes the discovery of such inhibitors.
Assuntos
Ácido Aspártico Endopeptidases/antagonistas & inibidores , Etilaminas/química , Inibidores de Proteases/química , Administração Oral , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Sítios de Ligação , Simulação por Computador , Cristalografia por Raios X , Etilaminas/síntese química , Etilaminas/farmacologia , Humanos , Camundongos , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Ratos , Relação Estrutura-Atividade , Tiazinas/química , Tiazinas/farmacologiaRESUMO
Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer's disease. We have recently disclosed a series of transition-state mimetic BACE-1 inhibitors showing nanomolar potency in cell-based assays. Amongst them, GSK188909 (compound 2) had favorable pharmacokinetics and was the first orally bioavailable inhibitor reported to demonstrate brain amyloid lowering in an animal model. In this Letter, we describe the reasons that led us to favor a second generation of inhibitors for further in vivo studies.
Assuntos
Ácido Aspártico Endopeptidases/antagonistas & inibidores , Inibidores de Proteases/química , Tiazinas/química , Administração Oral , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Sítios de Ligação , Simulação por Computador , Etilaminas/síntese química , Etilaminas/química , Etilaminas/farmacologia , Humanos , Camundongos , Inibidores de Proteases/farmacocinética , Ratos , Relação Estrutura-Atividade , Tiazinas/síntese química , Tiazinas/farmacocinéticaRESUMO
BACE-1 inhibition has the potential to provide a disease-modifying therapy for the treatment of Alzheimer's disease. Optimization of a first generation of BACE-1 inhibitors led to the discovery of novel hydroxyethylamines (HEAs) bearing a tricyclic nonprime side. These derivatives have nanomolar cell potency and are orally bioavailable.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Benzotiadiazinas/síntese química , Óxidos S-Cíclicos/síntese química , Etilaminas/síntese química , Administração Oral , Animais , Benzotiadiazinas/farmacocinética , Benzotiadiazinas/farmacologia , Disponibilidade Biológica , Óxidos S-Cíclicos/farmacocinética , Óxidos S-Cíclicos/farmacologia , Cães , Etilaminas/farmacocinética , Etilaminas/farmacologia , Modelos Moleculares , Ratos , Relação Estrutura-AtividadeRESUMO
This paper describes the discovery of non-peptidic, potent, and selective hydroxy ethylamine (HEA) inhibitors of BACE-1 by replacement of the prime side of a lead di-amide 2. Inhibitors with nanosmolar potency and high selectivity were identified. Depending on the nature of the P(1)(') and P(2)(') substituents, two different binding modes were observed in X-ray co-crystal structures.
Assuntos
Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Técnicas de Química Combinatória , Etilaminas/síntese química , Etilaminas/farmacologia , Doença de Alzheimer/tratamento farmacológico , Precursor de Proteína beta-Amiloide/antagonistas & inibidores , Cristalografia por Raios X , Etilaminas/química , Humanos , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer's disease. Herein, is described the lead generation effort which resulted, with the support of X-ray crystallography, in the discovery of potent inhibitors based on a hydroxy ethylamine (HEA) transition-state mimetic. These inhibitors were capable of lowering amyloid production in a cell-based assay.
Assuntos
Doença de Alzheimer/metabolismo , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Técnicas de Química Combinatória , Etilaminas/síntese química , Etilaminas/farmacologia , Doença de Alzheimer/tratamento farmacológico , Precursor de Proteína beta-Amiloide/antagonistas & inibidores , Cristalografia por Raios X , Etilaminas/química , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
This article is focusing on further optimization of previously described hydroxy ethylamine (HEA) BACE-1 inhibitors obtained from a focused library with the support of X-ray crystallography. Optimization of the non-prime side of our inhibitors and introduction of a 6-membered sultam substituent binding to Asn-294 as well as a fluorine in the C-2 position led to derivatives with nanomolar potency in cell-based assays.
Assuntos
Doença de Alzheimer/metabolismo , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Técnicas de Química Combinatória , Etilaminas/síntese química , Etilaminas/farmacologia , Doença de Alzheimer/tratamento farmacológico , Precursor de Proteína beta-Amiloide/antagonistas & inibidores , Animais , Asparagina/química , Cristalografia por Raios X , Modelos Animais de Doenças , Etilaminas/química , Flúor/química , Camundongos , Estrutura Molecular , Nanotecnologia , Relação Estrutura-AtividadeRESUMO
[reaction: see text] Starting from readily available precursors, selenoglycosides derived from GalNAc, GlcNAc, and ManNAc were prepared by either a one- or a two-step process. The anomeric selenides underwent facile C-Se homolysis to provide the corresponding anomeric radicals, which were trapped with alkenes to give C-glycosides. This provides a general entry to alpha-C-glycosides based on 2-amino-2-deoxy sugars that is also applicable to disaccharide variants.
Assuntos
Amino Açúcares/síntese química , Monossacarídeos/síntese química , Dissacarídeos/química , Galactose/química , Glucose/química , Glicosídeos , Manose/química , Compostos de SelênioRESUMO
The synthesis of the Fmoc-protected C-glycosyl tyrosines 1 and 2, together with two other related C-glycosyl tyrosines, has been achieved. Key reactions involved (i) the reaction of a glycal with an organozinc reagent (carrying an aryl iodide function) in the presence of a Lewis acid to establish the C-glycosyl linkage and (ii) subsequent cross coupling of the aryl iodide to an alanyl zinc reagent (in the presence of a Pd(0) catalyst) to complete the construction of the alpha-amino acid moiety. Using solid-phase peptide synthesis methods, two units of the mannosyl derivative 1 (shown as L-Tyr[C-Ac(4)-alpha-D-Man]) have been incorporated (with four units of glycine) into the linear hexapeptide 3 which was then converted to the C(2)-symmetric cyclic oligopeptide 4.
RESUMO
A new strategy that employs an exocyclic stereocenter to effect diastereocontrol in the tethered aminohydroxylation (TA) reaction is applied to the stereoselective synthesis of a range of amino alcohols in good to excellent yields, and with anti selectivities of up to 20:1. The influence of the reaction conditions and substrate parameters on the level of diastereocontrol is described. Furthermore, an "inside alkoxy" model is employed to rationalize the sense and degree of stereoselectivity observed in these systems.
Assuntos
Aminas/química , Amino Álcoois/síntese química , Alcenos/química , Amino Álcoois/química , Compostos Heterocíclicos/química , Hidroxilação , EstereoisomerismoRESUMO
A novel osmium-catalysed oxidative cyclisation of 1,2-diols bearing a pendant vinyl silane affords THFs that contain silicon functionality at the ring junction. When the cyclisation occurs onto a vinyl benzyldimethylsilyl group, the resulting silyl group can act as a masked hydroxyl group and undergo a Fleming-Tamao type oxidation at a later stage to form the corresponding lactol. The scope of this reaction can also be extended beyond 1,2-diols and applied to the cyclisation of α-hydroxy-sulfonamides and α-hydroxy-amides.