RESUMEN
Mutations in leucine-rich repeat kinase 2 (LRRK2) that increase its kinase activity are strongly linked to genetic forms of Parkinson's disease (PD). However, the regulation of endogenous wild-type (WT) LRRK2 kinase activity remains poorly understood, despite its frequent elevation in idiopathic PD (iPD) patients. Various stressors such as mitochondrial dysfunction, lysosomal dyshomeostasis, or vesicle trafficking deficits can activate WT LRRK2 kinase, but the specific molecular mechanisms are not fully understood. We found that the production of 4-hydroxynonenal (4-HNE), a lipid hydroperoxidation end-product, is a common biochemical response to these diverse stimuli. 4-HNE forms post-translational adducts with Cys2024 and Cys2025 in the kinase activation loop of WT LRRK2, significantly increasing its kinase activity. Additionally, we discovered that the 4-HNE responsible for regulating LRRK2 is generated by the action of 15-lipoxygenase (15-LO), making 15-LO an upstream regulator of the pathogenic hyperactivation of LRRK2 kinase activity. Pharmacological inhibition or genetic ablation of 15-LO prevents 4-HNE post-translational modification of LRRK2 kinase and its subsequent pathogenic hyperactivation. Therefore, 15-LO inhibitors, or methods to lower 4-HNE levels, or the targeting of Cys2024/2025 could provide new therapeutic strategies to modulate LRRK2 kinase activity and treat PD.
RESUMEN
Phosphatidylinositol (PI) is the precursor lipid for the minor phosphoinositides (PPIns), which are critical for multiple functions in all eukaryotic cells. It is poorly understood how phosphatidylinositol, which is synthesized in the ER, reaches those membranes where PPIns are formed. Here, we used VT01454, a recently identified inhibitor of class I PI transfer proteins (PITPs), to unravel their roles in lipid metabolism, and solved the structure of inhibitor-bound PITPNA to gain insight into the mode of inhibition. We found that class I PITPs not only distribute PI for PPIns production in various organelles such as the plasma membrane (PM) and late endosomes/lysosomes, but that their inhibition also significantly reduced the levels of phosphatidylserine, di- and triacylglycerols, and other lipids, and caused prominent increases in phosphatidic acid. While VT01454 did not inhibit Golgi PI4P formation nor reduce resting PM PI(4,5)P2 levels, the recovery of the PM pool of PI(4,5)P2 after receptor-mediated hydrolysis required both class I and class II PITPs. Overall, these studies show that class I PITPs differentially regulate phosphoinositide pools and affect the overall cellular lipid landscape.
Asunto(s)
Fosfatidilinositoles , Proteínas de Transferencia de Fosfolípidos , Humanos , Fosfatidilinositoles/metabolismo , Proteínas de Transferencia de Fosfolípidos/metabolismo , Proteínas de Transferencia de Fosfolípidos/genética , Metabolismo de los Lípidos , Membrana Celular/metabolismo , Células HeLa , Orgánulos/metabolismo , Endosomas/metabolismo , AnimalesRESUMEN
The Hippo pathway plays a key role in development, organ size control and tissue homeostasis, and its dysregulation contributes to cancer. The LATS tumor suppressor kinases phosphorylate and inhibit the YAP/TAZ transcriptional co-activators to suppress gene expression and cell growth. Through a screen of marine natural products, we identified microcolin B (MCB) as a Hippo activator that preferentially kills YAP-dependent cancer cells. Structure-activity optimization yielded more potent MCB analogs, which led to the identification of phosphatidylinositol transfer proteins α and ß (PITPα/ß) as the direct molecular targets. We established a critical role of PITPα/ß in regulating LATS and YAP. Moreover, we showed that PITPα/ß influence the Hippo pathway via plasma membrane phosphatidylinositol-4-phosphate. This study uncovers a previously unrecognized role of PITPα/ß in Hippo pathway regulation and as potential cancer therapeutic targets.
Asunto(s)
Productos Biológicos , Neoplasias , Humanos , Vía de Señalización Hippo , Fosfatidilinositoles , Proteínas de Transferencia de Fosfolípidos/metabolismo , Fosfoproteínas/metabolismo , Proteínas Serina-Treonina Quinasas , Transducción de Señal , Factores de Transcripción/metabolismoRESUMEN
Extensive knowledge has been gained on the transcription network controlled by ERα, however, the mechanism underlying ESR1 (encoding ERα) expression is less understood. We recently discovered that the Hippo pathway is required for the proper expression of ESR1. YAP/TAZ are transcription coactivators that are phosphorylated and inhibited by the Hippo pathway kinase LATS. Here we delineated the molecular mechanisms underlying ESR1 transcription repression by the Hippo pathway. Mechanistically, YAP binds to TEAD to increase local chromatin accessibility to stimulate transcription of nearby genes. Among the YAP target genes, Vestigial-Like Protein 3 (VGLL3) competes with YAP/TAZ for binding to TEAD transcription factor and recruits the NCOR2/SMRT repressor to the super-enhancer of ESR1 gene, leading to epigenetic alteration and transcriptional silencing. We developed a potent LATS inhibitor VT02956. Targeting the Hippo pathway by VT02956 represses ESR1 expression and inhibits the growth of ER+ breast cancer cells as well as patient-derived tumour organoids. Moreover, histone deacetylase inhibitors, such as Entinostat, induce VGLL3 expression to inhibit ER+ breast cancer cells. Our study suggests LATS as unexpected cancer therapeutic targets, especially for endocrine-resistant breast cancers.
Asunto(s)
Neoplasias de la Mama , Receptor alfa de Estrógeno , Vía de Señalización Hippo , Femenino , Humanos , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas Señalizadoras YAP/metabolismoRESUMEN
Mutations in the neurofibromatosis type 2 (NF2) gene that limit or abrogate expression of functional Merlin are common in malignant mesothelioma. Merlin activates the Hippo pathway to suppress nuclear translocation of YAP and TAZ, the major effectors of the pathway that associate with the TEAD transcription factors in the nucleus and promote expression of genes involved in cell proliferation and survival. In this article, we describe the discovery of compounds that selectively inhibit YAP/TAZ-TEAD promoted gene transcription, block TEAD auto-palmitoylation, and disrupt interaction between YAP/TAZ and TEAD. Optimization led to potent analogs with excellent oral bioavailability and pharmacokinetics that selectively inhibit NF2-deficient mesothelioma cell proliferation in vitro and growth of subcutaneous tumor xenografts in vivo These highly potent and selective TEAD inhibitors provide a way to target the Hippo-YAP pathway, which thus far has been undruggable and is dysregulated frequently in malignant mesothelioma and in other YAP-driven cancers and diseases.
Asunto(s)
Mesotelioma Maligno/tratamiento farmacológico , Factores de Transcripción de Dominio TEA/antagonistas & inhibidores , Animales , Proliferación Celular , Humanos , Lipoilación , Mesotelioma Maligno/genética , Ratones , Transducción de SeñalRESUMEN
UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a Zn2+ deacetylase that is essential for the survival of most pathogenic Gram-negative bacteria. ACHN-975 (N-((S)-3-amino-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)-4-(((1R,2R)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzamide) was the first LpxC inhibitor to reach human clinical testing and was discovered to have a dose-limiting cardiovascular toxicity of transient hypotension without compensatory tachycardia. Herein we report the effort beyond ACHN-975 to discover LpxC inhibitors optimized for enzyme potency, antibacterial activity, pharmacokinetics, and cardiovascular safety. Based on its overall profile, compound 26 (LPXC-516, (S)-N-(2-(hydroxyamino)-1-(3-methoxy-1,1-dioxidothietan-3-yl)-2-oxoethyl)-4-(6-hydroxyhexa-1,3-diyn-1-yl)benzamide) was chosen for further development. A phosphate prodrug of 26 was developed that provided a solubility of >30â mg mL-1 for parenteral administration and conversion into the active drug with a t1/2 of approximately two minutes. Unexpectedly, and despite our optimization efforts, the prodrug of 26 still possesses a therapeutic window insufficient to support further clinical development.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Antibacterianos/farmacología , Diinos/farmacología , Inhibidores Enzimáticos/farmacología , Corazón/efectos de los fármacos , Ácidos Hidroxámicos/farmacología , Animales , Antibacterianos/síntesis química , Antibacterianos/farmacocinética , Antibacterianos/toxicidad , Proteínas Bacterianas/antagonistas & inhibidores , Cardiotoxicidad , Diinos/síntesis química , Diinos/farmacocinética , Diinos/toxicidad , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/toxicidad , Ácidos Hidroxámicos/síntesis química , Ácidos Hidroxámicos/farmacocinética , Ácidos Hidroxámicos/toxicidad , Masculino , Estructura Molecular , Profármacos/síntesis química , Profármacos/farmacocinética , Profármacos/farmacología , Profármacos/toxicidad , Pseudomonas aeruginosa/efectos de los fármacos , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Porphyromonas gingivalis, the keystone pathogen in chronic periodontitis, was identified in the brain of Alzheimer's disease patients. Toxic proteases from the bacterium called gingipains were also identified in the brain of Alzheimer's patients, and levels correlated with tau and ubiquitin pathology. Oral P. gingivalis infection in mice resulted in brain colonization and increased production of Aß1-42, a component of amyloid plaques. Further, gingipains were neurotoxic in vivo and in vitro, exerting detrimental effects on tau, a protein needed for normal neuronal function. To block this neurotoxicity, we designed and synthesized small-molecule inhibitors targeting gingipains. Gingipain inhibition reduced the bacterial load of an established P. gingivalis brain infection, blocked Aß1-42 production, reduced neuroinflammation, and rescued neurons in the hippocampus. These data suggest that gingipain inhibitors could be valuable for treating P. gingivalis brain colonization and neurodegeneration in Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/microbiología , Infecciones por Bacteroidaceae/tratamiento farmacológico , Encéfalo/microbiología , Encéfalo/patología , Fármacos Neuroprotectores/uso terapéutico , Porphyromonas gingivalis/enzimología , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Anciano , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Animales , Infecciones por Bacteroidaceae/microbiología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Femenino , Cisteína-Endopeptidasas Gingipaínas/antagonistas & inhibidores , Cisteína-Endopeptidasas Gingipaínas/metabolismo , Cisteína-Endopeptidasas Gingipaínas/farmacología , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Persona de Mediana Edad , Fármacos Neuroprotectores/farmacología , Fragmentos de Péptidos/metabolismo , Proyectos Piloto , Porphyromonas gingivalis/efectos de los fármacos , Porphyromonas gingivalis/genética , Estudios Prospectivos , Saliva/microbiología , Bibliotecas de Moléculas Pequeñas/farmacología , Proteínas tau/metabolismoRESUMEN
The structure activity relationship of the prime region of conformationally restricted hydroxyethylamine (HEA) BACE inhibitors is described. Variation of the P1' region provided selectivity over Cat-D with a series of 2,2-dioxo-isothiochromanes and optimization of the P2' substituent of chromane-HEA(s) with polar substituents provided improvements in the compound's in vitro permeability. Significant potency gains were observed with small aliphatic substituents such as methyl, n-propyl, and cyclopropyl when placed at the C-2 position of the chromane.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Cromanos/química , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Sitios de Unión , Células Cultivadas , Etilaminas/síntesis química , Etilaminas/química , Etilaminas/farmacología , Concentración 50 Inhibidora , Modelos Moleculares , Relación Estructura-ActividadRESUMEN
Surface Plasmon Resonance (SPR) is rarely used as a primary High-throughput Screening (HTS) tool in fragment-based approaches. With SPR instruments becoming increasingly high-throughput it is now possible to use SPR as a primary tool for fragment finding. SPR becomes, therefore, a valuable tool in the screening of difficult targets such as the ubiquitin E3 ligase Parkin. As a prerequisite for the screen, a large number of SPR tests were performed to characterize and validate the active form of Parkin. A set of compounds was designed and used to define optimal SPR assay conditions for this fragment screen. Using these conditions, more than 5000 pre-selected fragments from our in-house library were screened for binding to Parkin. Additionally, all fragments were simultaneously screened for binding to two off target proteins to exclude promiscuous binding compounds. A low hit rate was observed that is in line with hit rates usually obtained by other HTS screening assays. All hits were further tested in dose responses on the target protein by SPR for confirmation before channeling the hits into Nuclear Magnetic Resonance (NMR) and other hit-confirmation assays.
Asunto(s)
Ensayos Analíticos de Alto Rendimiento , Fragmentos de Péptidos/química , Resonancia por Plasmón de Superficie , Ubiquitina-Proteína Ligasas/química , Ditiotreitol/química , Ditiotreitol/metabolismo , Descubrimiento de Drogas , Ensayos Analíticos de Alto Rendimiento/métodos , Cinética , Ligandos , Resonancia Magnética Nuclear Biomolecular , Fragmentos de Péptidos/metabolismo , Unión Proteica , Sustancias Reductoras/química , Sustancias Reductoras/metabolismo , Resonancia por Plasmón de Superficie/métodos , Ubiquitina-Proteína Ligasas/antagonistas & inhibidores , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Polo-like kinase-2 (Plk-2) has been implicated as the dominant kinase involved in the phosphorylation of α-synuclein in Lewy bodies, which are one of the hallmarks of Parkinson's disease neuropathology. Potent, selective, brain-penetrant inhibitors of Plk-2 were obtained from a structure-guided drug discovery approach driven by the first reported Plk-2-inhibitor complexes. The best of these compounds showed excellent isoform and kinome-wide selectivity, with physicochemical properties sufficient to interrogate the role of Plk-2 inhibition inâ vivo. One such compound significantly decreased phosphorylation of α-synuclein in rat brain upon oral administration and represents a useful probe for future studies of this therapeutic avenue toward the potential treatment of Parkinson's disease.
Asunto(s)
Encéfalo/metabolismo , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , alfa-Sinucleína/metabolismo , Animales , Sitios de Unión , Barrera Hematoencefálica/metabolismo , Femenino , Células HEK293 , Semivida , Humanos , Masculino , Ratones , Simulación de Dinámica Molecular , Fosforilación/efectos de los fármacos , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Serina-Treonina Quinasas/metabolismo , Estructura Terciaria de Proteína , Ratas , Ratas Sprague-DawleyRESUMEN
A series of potent α4ß1/α4ß7 integrin inhibitors is reported, including an inhibitor 12d with remarkable oral exposure and efficacy in rat models of rheumatoid arthritis and Crohn's disease.
Asunto(s)
Integrina alfa4beta1/antagonistas & inhibidores , Integrinas/antagonistas & inhibidores , Administración Oral , Animales , Área Bajo la Curva , Artritis Reumatoide/inducido químicamente , Artritis Reumatoide/tratamiento farmacológico , Enfermedad de Crohn/tratamiento farmacológico , Modelos Animales de Enfermedad , Semivida , Humanos , Integrina alfa4beta1/metabolismo , Integrinas/metabolismo , Células Jurkat , Microsomas Hepáticos/metabolismo , RatasRESUMEN
Mitsunobu reactions were employed to link t-butyl esters of α4 integrin inhibitors at each of the termini of a three-arm, 40 kDa, branched PEG. Cleavage of the t-butyl esters using HCO2H provided easily isolated PEG derivatives, which are potent α4 integrin inhibitors, and which achieve sustained levels and bioactivity in vivo, following subcutaneous administration to rats.
Asunto(s)
Integrina alfa4/química , Polietilenglicoles/química , Animales , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacocinética , Ésteres , Semivida , Humanos , Inyecciones Subcutáneas , Integrina alfa4/inmunología , Integrina alfa4/metabolismo , Células Jurkat , RatasRESUMEN
Herein, we describe our strategy to design metabolically stable γ-secretase inhibitors which are selective for inhibition of Aß generation over Notch. We highlight our synthetic strategy to incorporate diversity and chirality. Compounds 30 (ELND006) and 34 (ELND007) both entered human clinical trials. The in vitro and in vivo characteristics for these two compounds are described. A comparison of inhibition of Aß generation in vivo between 30, 34, Semagacestat 41, Begacestat 42, and Avagacestat 43 in mice is made. 30 lowered Aß in the CSF of healthy human volunteers.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Péptidos beta-Amiloides/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Compuestos Heterocíclicos con 3 Anillos/farmacología , Pirazoles/farmacología , Quinolinas/farmacología , Receptores Notch/antagonistas & inhibidores , Sulfonamidas/farmacología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Péptidos beta-Amiloides/metabolismo , Animales , Área Bajo la Curva , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Perros , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Estabilidad de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Expresión Génica/efectos de los fármacos , Compuestos Heterocíclicos con 3 Anillos/química , Proteínas de Homeodominio/genética , Humanos , Masculino , Ratones , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Modelos Químicos , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/farmacocinética , Quinolinas/síntesis química , Quinolinas/farmacocinética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores Notch/metabolismo , Relación Estructura-Actividad , Sulfonamidas/química , Factores de Tiempo , Factor de Transcripción HES-1RESUMEN
A series of (S)-2-(2-(diethylamino)-5-(N-alkyl-N-sulfonamido)pyrimidin-4-ylamino)-3-(4-(carbamoyloxy)phenyl)propanoic acid is discovered as orally available VLA-4 antagonists. Representative compounds 11b and 11p showed efficacy in multiple in vivo animal models. The in vitro selectivity of 11p is also described.
Asunto(s)
Antirreumáticos/farmacología , Integrina alfa4beta1/antagonistas & inhibidores , Pirimidinas/farmacología , Sulfonamidas/farmacología , Animales , Antirreumáticos/administración & dosificación , Antirreumáticos/síntesis química , Artritis Experimental/tratamiento farmacológico , Asma/tratamiento farmacológico , Adhesión Celular/efectos de los fármacos , Colágeno Tipo II/antagonistas & inhibidores , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Fibronectinas/química , Humanos , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Conformación Molecular , Esclerosis Múltiple/tratamiento farmacológico , Pirimidinas/administración & dosificación , Pirimidinas/síntesis química , Ratas , Ratas Endogámicas Lew , Ratas Sprague-Dawley , Relación Estructura-Actividad , Sulfonamidas/administración & dosificación , Sulfonamidas/síntesis químicaRESUMEN
The structure-activity relationship of a series of dihydroisoquinoline BACE-1 inhibitors is described. Application of structure-based design to screening hit 1 yielded sub-micromolar inhibitors. Replacement of the carboxylic acid of 1 was guided by X-ray crystallography, which allowed the replacement of a key water-mediated hydrogen bond. This work culminated in compounds such as 31, which possess good BACE-1 potency, excellent permeability and a low P-gp efflux ratio.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Ácido Aspártico/química , Diseño de Fármacos , Isoquinolinas/farmacología , Inhibidores de Proteasas/farmacología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Catálisis , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Isoquinolinas/síntesis química , Isoquinolinas/química , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/química , Relación Estructura-ActividadRESUMEN
Polo-like kinase-2 (Plk-2) is a potential therapeutic target for Parkinson's disease and this Letter describes the SAR of a series of dihydropteridinone based Plk-2 inhibitors. By optimizing both the N-8 substituent and the biaryl region of the inhibitors we obtained single digit nanomolar compounds such as 37 with excellent selectivity for Plk-2 over Plk-1. When dosed orally in rats, compound 37 demonstrated a 41-45% reduction of pS129-α-synuclein levels in the cerebral cortex.
Asunto(s)
Diseño de Fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Administración Oral , Animales , Encéfalo/metabolismo , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/metabolismo , Células HEK293 , Semivida , Humanos , Ratones , Microsomas Hepáticos/metabolismo , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/metabolismo , Pteridinas/síntesis química , Pteridinas/química , Pteridinas/farmacocinética , Ratas , Relación Estructura-Actividad , Quinasa Tipo Polo 1RESUMEN
Structure-activity relationship (SAR) of a novel, potent and metabolically stable series of benzo [3.2.1] bicyclic sulfonamide-pyrazoles as γ-secretase inhibitors are described. Compounds that are efficacious in reducing the cortical Aßx-40 levels in FVB mice via oral dose, as well as those with high selectivity over Notch, are highlighted.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Pirazoles/farmacología , Sulfonamidas/farmacología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Ratones , Pirazoles/química , Relación Estructura-Actividad , Sulfonamidas/químicaRESUMEN
The preparation of novel tetrahydro-1H-pyrazolo[4,3-c]pyridines is reported. Pivotal to the synthesis of these compounds was the development of mild reaction conditions to generate a highly functionalized nitrilimine capable of undergoing an intramolecular cycloaddition with a tethered alkyne. The desired cycloadduct was formed as an equal mixture of diastereomers.
Asunto(s)
Ciclización , Iminas/química , Nitrilos/química , Piridinas/síntesis química , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Modelos MolecularesRESUMEN
The structure-activity relationship (SAR) of a novel, potent and metabolically stable series of sulfonamide-pyrazoles that attenuate ß-amyloid peptide synthesis via γ-secretase inhibition is detailed herein. Sulfonamide-pyrazoles that are efficacious in reducing the cortical Aßx-40 levels in FVB mice via a single PO dose, as well as sulfonamide-pyrazoles that exhibit selectivity for inhibition of APP versus Notch processing by γ-secretase, are highlighted.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Precursor de Proteína beta-Amiloide/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Compuestos Heterocíclicos con 3 Anillos/farmacología , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , Péptidos beta-Amiloides/metabolismo , Animales , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/química , Compuestos Heterocíclicos con 3 Anillos/química , Concentración 50 Inhibidora , Ratones , Ratones Endogámicos , Relación Estructura-Actividad , Sulfonamidas/químicaRESUMEN
The SAR of a series of brain penetrant, trisubstituted thiophene based JNK inhibitors with improved pharmacokinetic properties is described. These compounds were designed based on information derived from metabolite identification studies which led to compounds such as 42 with lower clearance, greater brain exposure and longer half life compared to earlier analogs.