RESUMEN
Inhibition of the pituitary adenylate cyclase 1 receptor (PAC1R) is a novel mechanism that could be used for abortive treatment of acute migraine. Our research began with comparative analysis of known PAC1R ligand scaffolds, PACAP38 and Maxadilan, which resulted in the selection of des(24-42) Maxadilan, 6, as a starting point. C-terminal modifications of 6 improved the peptide metabolic stability in vitro and in vivo. SAR investigations identified synergistic combinations of amino acid replacements that significantly increased the in vitro PAC1R inhibitory activity of the analogs to the pM IC90 range. Our modifications further enabled deletion of up to six residues without impacting potency, thus improving peptide ligand binding efficiency. Analogs 17 and 18 exhibited robust in vivo efficacy in the rat Maxadilan-induced increase in blood flow (MIIBF) pharmacodynamic model at 0.3 mg/kg subcutaneous dosing. The first cocrystal structure of a PAC1R antagonist peptide (18) with PAC1R extracellular domain is reported.
Asunto(s)
Circulación Sanguínea/efectos de los fármacos , Péptidos/química , Péptidos/farmacología , Receptores del Polipéptido Activador de la Adenilato-Ciclasa Hipofisaria/antagonistas & inhibidores , Animales , Humanos , Proteínas de Insectos/farmacología , Masculino , Ratones , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/metabolismo , Trastornos Migrañosos/fisiopatología , Simulación del Acoplamiento Molecular , Péptidos/farmacocinética , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores del Polipéptido Activador de la Adenilato-Ciclasa Hipofisaria/química , Receptores del Polipéptido Activador de la Adenilato-Ciclasa Hipofisaria/metabolismo , Vasodilatadores/farmacologíaRESUMEN
We report the discovery of PDE10A PET tracer AMG 580 developed to support proof of concept studies with PDE10A inhibitors in the clinic. To find a tracer with higher binding potential (BPND) in NHP than our previously reported tracer 1, we implemented a surface plasmon resonance assay to measure the binding off-rate to identify candidates with slower washout rate in vivo. Five candidates (2-6) from two structurally distinct scaffolds were identified that possessed both the in vitro characteristics that would favor central penetration and the structural features necessary for PET isotope radiolabeling. Two cinnolines (2, 3) and one keto-benzimidazole (5) exhibited PDE10A target specificity and brain uptake comparable to or better than 1 in the in vivo LC-MS/MS kinetics distribution study in SD rats. In NHP PET imaging study, [(18)F]-5 produced a significantly improved BPND of 3.1 and was nominated as PDE10A PET tracer clinical candidate for further studies.
RESUMEN
INTRODUCTION: Phosphodiesterase 10A (PDE10A) is an intracellular enzyme responsible for the breakdown of cyclic nucleotides which are important second messengers for neurotransmission. Inhibition of PDE10A has been identified as a potential target for treatment of various neuropsychiatric disorders. To assist drug development, we have identified a selective PDE10A positron emission tomography (PET) tracer, AMG 580. We describe here the radiosynthesis of [(18)F]AMG 580 and in vitro and in vivo characterization results. METHODS: The potency and selectivity were determined by in vitro assay using [(3)H]AMG 580 and baboon brain tissues. [(18)F]AMG 580 was prepared by a 1-step [(18)F]fluorination procedure. Dynamic brain PET scans were performed in non-human primates. Regions-of-interest were defined on individuals' MRIs and transferred to the co-registered PET images. Data were analyzed using two tissue compartment analysis (2TC), Logan graphical (Logan) analysis with metabolite-corrected input function and the simplified reference tissue model (SRTM) method. A PDE10A inhibitor and unlabeled AMG 580 were used to demonstrate the PDE10A specificity. KD was estimated by Scatchard analysis of high and low affinity PET scans. RESULTS: AMG 580 has an in vitro KD of 71.9 pM. Autoradiography showed specific uptake in striatum. Mean activity of 121 ± 18 MBq was used in PET studies. In Rhesus, the baseline BPND for putamen and caudate was 3.38 and 2.34, respectively, via 2TC, and 3.16, 2.34 via Logan, and 2.92, and 2.01 via SRTM. A dose dependent decrease of BPND was observed by the pre-treatment with a PDE10A inhibitor. In baboons, 0.24 mg/kg dose of AMG 580 resulted in about 70% decrease of BPND. The in vivo KD of [(18)F]AMG 580 was estimated to be around 0.44 nM in baboons. CONCLUSION: [(18)F]AMG 580 is a selective and potent PDE10A PET tracer with excellent specific striatal binding in non-human primates. It warrants further evaluation in humans.
Asunto(s)
Aminopiridinas/farmacocinética , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Radioisótopos de Flúor/farmacocinética , Hidrolasas Diéster Fosfóricas/metabolismo , Tomografía de Emisión de Positrones/métodos , Radiofármacos/farmacocinética , Aminopiridinas/síntesis química , Animales , Autorradiografía , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Marcaje Isotópico , Cinética , Macaca mulatta , Masculino , Tasa de Depuración Metabólica , Papio , Radioquímica , Radiofármacos/síntesis química , Distribución TisularRESUMEN
Phosphodiesterase 10A (PDE10A) inhibitors have therapeutic potential for the treatment of psychiatric and neurologic disorders, such as schizophrenia and Huntington's disease. One of the key requirements for successful central nervous system drug development is to demonstrate target coverage of therapeutic candidates in brain for lead optimization in the drug discovery phase and for assisting dose selection in clinical development. Therefore, we identified AMG 580 [1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-fluoropropan-1-one], a novel, selective small-molecule antagonist with subnanomolar affinity for rat, primate, and human PDE10A. We showed that AMG 580 is suitable as a tracer for lead optimization to determine target coverage by novel PDE10A inhibitors using triple-stage quadrupole liquid chromatography-tandem mass spectrometry technology. [(3)H]AMG 580 bound with high affinity in a specific and saturable manner to both striatal homogenates and brain slices from rats, baboons, and human in vitro. Moreover, [(18)F]AMG 580 demonstrated prominent uptake by positron emission tomography in rats, suggesting that radiolabeled AMG 580 may be suitable for further development as a noninvasive radiotracer for target coverage measurements in clinical studies. These results indicate that AMG 580 is a potential imaging biomarker for mapping PDE10A distribution and ensuring target coverage by therapeutic PDE10A inhibitors in clinical studies.
Asunto(s)
Bencimidazoles/farmacología , Encéfalo/enzimología , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo , Tomografía de Emisión de Positrones/métodos , Pirazinas/farmacología , Animales , Bencimidazoles/farmacocinética , Encéfalo/diagnóstico por imagen , Cromatografía Liquida , Femenino , Radioisótopos de Flúor , Humanos , Masculino , Espectrometría de Masas , Estructura Molecular , Papio , Inhibidores de Fosfodiesterasa/química , Inhibidores de Fosfodiesterasa/farmacocinética , Unión Proteica , Pirazinas/farmacocinética , Ensayo de Unión Radioligante , Ratas Sprague-Dawley , Especificidad de la Especie , Estereoisomerismo , Resonancia por Plasmón de Superficie , Distribución TisularRESUMEN
We report the discovery of a novel series of 2-(3-alkoxy-1-azetidinyl) quinolines as potent and selective PDE10A inhibitors. Structure-activity studies improved the solubility (pH 7.4) and maintained high PDE10A activity compared to initial lead compound 3, with select compounds demonstrating good oral bioavailability. X-ray crystallographic studies revealed two distinct binding modes to the catalytic site of the PDE10A enzyme. An ex vivo receptor occupancy assay in rats demonstrated that this series of compounds covered the target within the striatum.
Asunto(s)
Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo , Quinolinas/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Modelos Moleculares , Estructura Molecular , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/química , Quinolinas/síntesis química , Quinolinas/química , Solubilidad , Relación Estructura-ActividadRESUMEN
We report the identification of a PDE10A clinical candidate by optimizing potency and in vivo efficacy of promising keto-benzimidazole leads 1 and 2. Significant increase in biochemical potency was observed when the saturated rings on morpholine 1 and N-acetyl piperazine 2 were changed by a single atom to tetrahydropyran 3 and N-acetyl piperidine 5. A second single atom modification from pyrazines 3 and 5 to pyridines 4 and 6 improved the inhibitory activity of 4 but not 6. In the in vivo LC-MS/MS target occupancy (TO) study at 10 mg/kg, 3, 5, and 6 achieved 86-91% occupancy of PDE10A in the brain. Furthermore, both CNS TO and efficacy in PCP-LMA behavioral model were observed in a dose dependent manner. With superior in vivo TO, in vivo efficacy and in vivo PK profiles in multiple preclinical species, compound 5 (AMG 579) was advanced as our PDE10A clinical candidate.
Asunto(s)
Antipsicóticos/química , Bencimidazoles/química , Inhibidores de Fosfodiesterasa/química , Hidrolasas Diéster Fosfóricas/metabolismo , Pirazinas/química , Administración Oral , Animales , Antipsicóticos/síntesis química , Antipsicóticos/farmacología , Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Disponibilidad Biológica , Encéfalo/metabolismo , Perros , Humanos , Masculino , Actividad Motora/efectos de los fármacos , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/química , Primates , Conformación Proteica , Pirazinas/síntesis química , Pirazinas/farmacología , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
We report the discovery of novel imidazo[4,5-b]pyridines as potent and selective inhibitors of PDE10A. The investigation began with our recently disclosed ketobenzimidazole 1, which exhibited single digit nanomolar PDE10A activity but poor oral bioavailability. To improve oral bioavailability, we turned to novel scaffold imidazo[4,5-b]pyridine 2, which not only retained nanomolar PDE10A activity but was also devoid of the morpholine metabolic liability. Structure-activity relationship studies were conducted systematically to examine how various regions of the molecule impacted potency. X-ray cocrystal structures of compounds 7 and 24 in human PDE10A helped to elucidate the key bonding interactions. Five of the most potent and structurally diverse imidazo[4,5-b]pyridines (4, 7, 12b, 24a, and 24b) with PDE10A IC50 values ranging from 0.8 to 6.7 nM were advanced into receptor occupancy studies. Four of them (4, 12b, 24a, and 24b) achieved 55-74% RO at 10 mg/kg po.
RESUMEN
INTRODUCTION: Phosphodiesterase 10A (PDE10A) is an intracellular enzyme responsible for the breakdown of cyclic nucleotides which are important secondary messengers in the central nervous system. Inhibition of PDE10A has been identified as a potential therapeutic target for treatment of various neuropsychiatric disorders. To assist the drug development program, we have identified a selective PDE10A PET tracer, [(11)C]AMG 7980, for imaging PDE10A distribution using positron emission tomography. METHODS: [(11)C]AMG 7980 was prepared in a one-pot, two-step reaction. Dynamic PET scans were performed in non-human primates following a bolus or bolus plus constant infusion tracer injection paradigm. Regions-of-interest were defined on individuals' MRIs and transferred to the co-registered PET images. Data were analyzed using Logan graphical analysis with metabolite-corrected input function, the simplified reference tissue model (SRTM) method and occupancy plots. A benchmark PDE10A inhibitor was used to demonstrate PDE10A-specific binding. RESULTS: [(11)C]AMG 7980 was prepared with a mean specific activity of 99 ± 74 GBq/µmol (n=10) and a synthesis time of 45 min. Specific binding of the tracer was localized to the striatum and globus pallidus (GP) and low in other brain regions. Thalamus was used as the reference tissue to derive binding potentials (BPND). The BPND for caudate, putamen, and GP were 0.23, 0.65, 0.51, respectively by the graphical method, and 0.42, 0.76, and 0.75 from the SRTM method. A dose dependent decrease of BPND was observed with the pre-treatment of a PDE10A inhibitor. A bolus plus infusion injection paradigm yielded similar results. CONCLUSION: [(11)C]AMG 7980 has been successfully used for imaging PDE10A in non-human primate brain. Despite the fast brain kinetics it can be used to measure target occupancy of PDE10A inhibitors in non-human primates and potentially applicable to humans.
Asunto(s)
Aminopiridinas , Hidrolasas Diéster Fosfóricas/metabolismo , Tomografía de Emisión de Positrones/métodos , Piridazinas , Aminopiridinas/síntesis química , Aminopiridinas/química , Aminopiridinas/metabolismo , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Radioisótopos de Carbono , Estudios de Factibilidad , Cinética , Masculino , Papio , Piridazinas/síntesis química , Piridazinas/química , Piridazinas/metabolismo , RadioquímicaRESUMEN
Our development of PDE10A inhibitors began with an HTS screening hit (1) that exhibited both high p-glycoprotein (P-gp) efflux ratios in rat and human and poor metabolic stability. On the basis of cocrystal structure of 1 in human PDE10A enzyme, we designed a novel keto-benzimidazole 26 with comparable PDE10A potency devoid of efflux liabilities. On target in vivo coverage of PDE10A in rat brain was assessed using our previously reported LC-MS/MS receptor occupancy (RO) technology. Compound 26 achieved 55% RO of PDE10A at 30 mg/kg po and covered PDE10A receptors in rat brain in a dose-dependent manner. Cocrystal structure of 26 in PDE10A confirmed the binding mode of the novel scaffold. Further optimization resulted in the identification of keto-benzimidazole 34, which showed an increased in vivo efficacy of 57% RO in rats at 10 mg/kg po and an improved in vivo rat clearance and oral bioavailability.
Asunto(s)
Bencimidazoles/farmacología , Diseño de Fármacos , Cetonas/farmacología , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo , Animales , Bencimidazoles/administración & dosificación , Bencimidazoles/síntesis química , Células Cultivadas , Relación Dosis-Respuesta a Droga , Humanos , Cetonas/administración & dosificación , Cetonas/síntesis química , Masculino , Modelos Moleculares , Estructura Molecular , Inhibidores de Fosfodiesterasa/administración & dosificación , Inhibidores de Fosfodiesterasa/síntesis química , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , PorcinosRESUMEN
We report the discovery of a novel series of biaryl ethers as potent and selective PDE10A inhibitors. Structure-activity studies improved the potency and decreased Pgp-mediated efflux found in the initial compound 4. X-ray crystallographic studies revealed two novel binding modes to the catalytic site of the PDE10A enzyme.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Descubrimiento de Drogas , Éteres/metabolismo , Éteres/farmacología , Inhibidores de Fosfodiesterasa/metabolismo , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Éteres/síntesis química , Éteres/química , Humanos , Modelos Moleculares , Estructura Molecular , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/química , Relación Estructura-ActividadRESUMEN
We report our successful effort to increase the PDE3 selectivity of PDE10A inhibitor pyridyl cinnoline 1 using a combination of computational modeling and structural-activity relationship investigations. An analysis of the PDE3 catalytic domain compared to the co-crystal structure of cinnoline analog 1 in PDE10A revealed two areas of structural differences in the active sites and suggested areas on the scaffold that could be modified to exploit those unique structural features. Once SAR established the cinnoline as the optimal scaffold, modifications on the methoxy groups of the cinnoline and the methyl group on the pyridine led to the discovery of compounds 33 and 36. Both compounds achieved significant improvement in selectivity against PDE3 while maintaining their PDE10A inhibitory activity and in vivo metabolic stability comparable to 1.
Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 3/química , Compuestos Heterocíclicos con 2 Anillos/química , Inhibidores de Fosfodiesterasa/química , Hidrolasas Diéster Fosfóricas/química , Piridinas/química , Animales , Sitios de Unión , Dominio Catalítico , Cristalografía por Rayos X , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 3/metabolismo , Diseño de Fármacos , Semivida , Compuestos Heterocíclicos con 2 Anillos/síntesis química , Compuestos Heterocíclicos con 2 Anillos/farmacocinética , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/farmacocinética , Hidrolasas Diéster Fosfóricas/metabolismo , Piridinas/síntesis química , Piridinas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
A radiolabeled tracer for imaging therapeutic targets in the brain is a valuable tool for lead optimization in CNS drug discovery and for dose selection in clinical development. We report the rapid identification of a novel phosphodiesterase 10A (PDE10A) tracer candidate using a LC-MS/MS technology. This structurally distinct PDE10A tracer, AMG-7980 (5), has been shown to have good uptake in the striatum (1.2% ID/g tissue), high specificity (striatum/thalamus ratio of 10), and saturable binding in vivo. The PDE10A affinity (K(D)) and PDE10A target density (B(max)) were determined to be 0.94 nM and 2.3 pmol/mg protein, respectively, using [(3)H]5 on rat striatum homogenate. Autoradiography on rat brain sections indicated that the tracer signal was consistent with known PDE10A expression pattern. The specific binding of [(3)H]5 to rat brain was blocked by another structurally distinct, published PDE10A inhibitor, MP-10. Lastly, our tracer was used to measure in vivo PDE10A target occupancy of a PDE10A inhibitor in rats using LC-MS/MS technology.
Asunto(s)
Aminopiridinas/síntesis química , Hidrolasas Diéster Fosfóricas/metabolismo , Piridazinas/síntesis química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Aminopiridinas/química , Aminopiridinas/farmacocinética , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/enzimología , Línea Celular , Cromatografía Liquida , Perros , Humanos , Técnicas In Vitro , Masculino , Permeabilidad , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/química , Inhibidores de Fosfodiesterasa/farmacocinética , Unión Proteica , Pirazoles/farmacocinética , Piridazinas/química , Piridazinas/farmacocinética , Quinolinas/farmacocinética , Cintigrafía , Radiofármacos/síntesis química , Radiofármacos/química , Radiofármacos/farmacocinética , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Resonancia por Plasmón de Superficie , Espectrometría de Masas en Tándem , Distribución Tisular , TritioRESUMEN
We report the discovery of 6,7-dimethoxy-4-(pyridin-3-yl)cinnolines as novel inhibitors of phosphodiesterase 10A (PDE10A). Systematic examination and analyses of structure-activity-relationships resulted in single digit nM potency against PDE10A. X-ray co-crystal structure revealed the mode of binding in the enzyme's catalytic domain and the source of selectivity against other PDEs. High in vivo clearance in rats was addressed with the help of metabolite identification (ID) studies. These findings combined resulted in compound 39, a promising potent inhibitor of PDE10A with good in vivo metabolic stability in rats and efficacy in a rodent behavioral model.
Asunto(s)
Cumarinas/síntesis química , Inhibidores de Fosfodiesterasa/síntesis química , Hidrolasas Diéster Fosfóricas/metabolismo , Psicotrópicos/síntesis química , Animales , Reacción de Prevención/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Sitios de Unión , Cumarinas/farmacología , Descubrimiento de Drogas , Humanos , Modelos Moleculares , Inhibidores de Fosfodiesterasa/administración & dosificación , Unión Proteica , Psicotrópicos/administración & dosificación , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
A series of [1,2,4]triazolo[3,4-f][1,6]naphthyridine allosteric dual inhibitors of Akt1 and 2 have been developed. These compounds have been shown to have potent dual Akt1 and 2 cell potency. The representative compound 13 provided potent inhibitory activity against Akt1 and 2 in vivo in a mouse model.
Asunto(s)
Química Farmacéutica/métodos , Naftiridinas/química , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Triazoles/química , Sitio Alostérico , Animales , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/metabolismo , Concentración 50 Inhibidora , Pulmón/efectos de los fármacos , Ratones , Modelos Químicos , Proteínas Proto-Oncogénicas c-akt/química , Relación Estructura-ActividadRESUMEN
Deregulation of the receptor tyrosine kinase c-Kit is associated with an increasing number of human diseases, including certain cancers and mast cell diseases. Interference of c-Kit signaling with multi-kinase inhibitors has been shown clinically to successfully treat gastrointestinal stromal tumors and mastocytosis. Targeted therapy of c-Kit activity may provide therapeutic advantages against off-target effects for non-oncology applications. A new structural class of c-Kit inhibitors is described, including in vitro c-Kit potency, kinase selectivity, and the observed binding mode.
Asunto(s)
Amidas/síntesis química , Amidas/farmacología , Isoxazoles/síntesis química , Isoxazoles/farmacología , Proteínas Proto-Oncogénicas c-kit/efectos de los fármacos , Proteínas Proto-Oncogénicas c-kit/metabolismo , Amidas/química , Técnicas Químicas Combinatorias , Cristalografía por Rayos X , Humanos , Isoxazoles/química , Conformación Molecular , Estructura Molecular , Proteínas Tirosina Quinasas Receptoras/metabolismo , Relación Estructura-Actividad , Proteínas Quinasas p38 Activadas por Mitógenos/efectos de los fármacosRESUMEN
A potent and selective c-Kit inhibitor 20 was identified through a structure-activity relationship study. In an in vivo mouse model of mast cell activation, 20 blocked the SCF-induced histamine release with an EC(50) of 26 nM.
Asunto(s)
Química Farmacéutica/métodos , Inflamación/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-kit/química , Animales , Diseño de Fármacos , Liberación de Histamina/efectos de los fármacos , Concentración 50 Inhibidora , Cinética , Sistema de Señalización de MAP Quinasas , Mastocitos/metabolismo , Ratones , Ratas , Factor de Células Madre/metabolismo , Relación Estructura-ActividadRESUMEN
Inhibition of c-Kit has the potential to treat mast cell associated fibrotic diseases. We report the discovery of several aminoquinazoline pyridones that are potent inhibitors of c-Kit with greater than 200-fold selectivity against KDR, p38, Lck, and Src. In vivo efficacy of pyridone 16 by dose-dependent inhibition of histamine release was demonstrated in a rodent pharmacodynamic model of mast cell activation.
Asunto(s)
Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Proto-Oncogénicas c-kit/metabolismo , Piridonas/síntesis química , Quinazolinas/síntesis química , Administración Oral , Animales , Cristalografía por Rayos X , Liberación de Histamina/efectos de los fármacos , Mastocitos/efectos de los fármacos , Mastocitos/metabolismo , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/farmacología , Piridonas/farmacocinética , Piridonas/farmacología , Quinazolinas/farmacocinética , Quinazolinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
The enantioselective total synthesis of callipeltoside A is described. Two syntheses of the macrolactone subunit are included: the first relies upon an Ireland-Claisen rearrangement to generate the trisubstituted olefin geometry and the second utilizes an enantioselective vinylogous aldol reaction for this purpose. Enantioselective syntheses of the sugar and chlorocyclopropane side chain fragments are also disclosed. The relative and absolute stereochemistry of this natural product was determined by fragment coupling with the two enantiomers of the side chain fragment.
RESUMEN
Pyrimidine methyl anilines as potent and selective mGlu2 potentiators are described. Findings from the structure-activity-relationship investigations are discussed.
Asunto(s)
Compuestos de Anilina/síntesis química , Pirimidinas/síntesis química , Receptores de Glutamato Metabotrópico/agonistas , Compuestos de Anilina/química , Compuestos de Anilina/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Ensayo de Unión Radioligante , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química , Sulfonamidas/farmacologíaRESUMEN
An asymmetric total synthesis of callipeltoside A has been accomplished highlighted by a catalytic enantioselective vinylogous aldol reaction and a boron-mediated anti-aldol reaction influenced by remote stereocontrol.