RESUMEN
The development of renin inhibitors with favorable oral pharmacokinetic profiles has been a longstanding challenge for the pharmaceutical industry. As part of our work to identify inhibitors of BACE1, we have previously developed iminopyrimidinones as a novel pharmacophore for aspartyl protease inhibition. In this letter we describe how we modified substitution around this pharmacophore to develop a potent, selective and orally active renin inhibitor.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Iminas/farmacología , Pirimidinonas/farmacología , Renina/antagonistas & inhibidores , Administración Oral , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Iminas/síntesis química , Iminas/química , Modelos Moleculares , Estructura Molecular , Pirimidinonas/síntesis química , Pirimidinonas/química , Renina/metabolismo , Relación Estructura-ActividadRESUMEN
In-vitro studies are widely used in nutrition research. Two major challenges using in-vitro models in animal nutrition research are the individual adaptation of in-vitro digestion models to varying physiological conditions and small digesta output limiting sample material for further analysis. Since several years, the use of zinc in animal production has been legally reduced to control zinc emissions. Earlier, zinc doses around 3000 mg/kg diet were used to prevent post-weaning diarrhea and promote growth in weaning piglets. The first aim of this study was to adapt an in-vitro digestion system for piglets with increased sample output. The second aim was to study the effect of a titanium-bound zinc source at legal dietary inclusion levels on nutrient degradation in an in-vitro digestion model. The experiment was conducted in a 2x2 factorial design incubating 2 different feeds (1. control feed: a commercial piglet diet containing 75 mg zinc per kg diet and 2. treatment feed: control feed with 50 mg of a titanium-bound zinc oxide) in in-situ digestion bags in the Ankom Daisy® incubator with or without digestive enzymes (pepsin, pancreatic enzymes and bile salts). Residuals of incubated feed were analyzed for crude ash, crude protein and starch. The addition of pepsin, pancreatic enzymes and bile salts significantly increased organic matter, crude protein and starch degradation from the digested feed, therefore making the distinction of nutrient disappearance due to enzyme activity versus due to dissolution possible. In conclusion we established an in-vitro digestion model to evaluate the effect of addition of a new zinc source on the enzymatic digestion in piglets. However, addition of the new zinc source did not significantly improve nutrient degradation in the in-vitro digestion model.
RESUMEN
In an attempt to further improve overall profiles of the oxadiazine series of GSMs, in particular the hERG activity, conformational modifications of the core structure resulted in the identification of fused oxadiazepines such as 7i which had an improved hERG inhibition profile and was a highly efficacious GSM in vitro and in vivo in rats. These SAR explorations offer opportunities to identify potential drugs to treat Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Azepinas/síntesis química , Descubrimiento de Drogas , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Animales , Azepinas/química , Azepinas/farmacología , Canal de Potasio ERG1 , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
From an initial lead 1, a structure-based design approach led to identification of a novel, high-affinity iminohydantoin BACE1 inhibitor that lowers CNS-derived Aß following oral administration to rats. Herein we report SAR development in the S3 and F' subsites of BACE1 for this series, the synthetic approaches employed in this effort, and in vivo data for the optimized compound.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Péptidos beta-Amiloides/antagonistas & inhibidores , Anticonvulsivantes/síntesis química , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Hidantoínas/síntesis química , Administración Oral , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/líquido cefalorraquídeo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/sangre , Péptidos beta-Amiloides/líquido cefalorraquídeo , Animales , Anticonvulsivantes/farmacología , Ácido Aspártico Endopeptidasas/metabolismo , Sitios de Unión , Simulación por Computador , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Humanos , Hidantoínas/farmacología , Modelos Moleculares , Unión Proteica , Ratas , Ratas Sprague-DawleyRESUMEN
Novel P2X(7) antagonists were developed using a purine scaffold. These compounds were potent and selective at the P2X(7) receptor in human and rodent as well as efficacious in rodent pain models. Compound 15a was identified to have oral potency in several pain models in rodent similar to naproxen, gabapentin and pregabalin. Structure-activity relationship (SAR) development and results of pain models are presented.
Asunto(s)
Dolor/tratamiento farmacológico , Antagonistas del Receptor Purinérgico P2X/síntesis química , Purinas/síntesis química , Receptores Purinérgicos P2X7/química , Animales , Humanos , Antagonistas del Receptor Purinérgico P2X/química , Antagonistas del Receptor Purinérgico P2X/uso terapéutico , Purinas/química , Purinas/uso terapéutico , Ratas , Receptores Purinérgicos P2X7/metabolismo , Relación Estructura-ActividadRESUMEN
A series of spiro-azetidines and azetidinones has been evaluated as novel blockers of the T-type calcium channel (Ca(V)3.2) which is a new therapeutic target for the potential treatment of both inflammatory and neuropathic pain. Confirmation and optimization of the potency, selectivity and DMPK properties of leads will be described.
Asunto(s)
Azetidinas/química , Bloqueadores de los Canales de Calcio/síntesis química , Canales de Calcio Tipo T/química , Piperidinas/química , Compuestos de Espiro/química , Animales , Azetidinas/síntesis química , Azetidinas/uso terapéutico , Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/uso terapéutico , Canales de Calcio Tipo T/metabolismo , Diseño de Fármacos , Humanos , Dolor/tratamiento farmacológico , Unión Proteica , Ratas , Relación Estructura-ActividadRESUMEN
A class of novel 2-aminobenzothiazoles have been identified as NPY Y(1) antagonists. Various N-heterocyclic substituted aminophenethyl-2-aminobenzothiazole analogs were synthesized to explore the SAR. Isothiourea analogs and ligands with high potency (K(i) 30 nM) have been identified.
Asunto(s)
Descubrimiento de Drogas , Receptores de Neuropéptido Y/antagonistas & inhibidores , Tiourea/farmacología , Ciclización , Relación Dosis-Respuesta a Droga , Ligandos , Estructura Molecular , Estereoisomerismo , Relación Estructura-Actividad , Tiourea/análogos & derivados , Tiourea/químicaRESUMEN
A series of novel 1,3-benzodiazapine based D1 antagonists was designed according to the understanding of pharmacophore models derived from SCH 23390 (1b), a potent and selective D1 antagonist. The new design features an achiral cyclic-amidine that maintains desired basicity. Solid phase synthesis was developed for SAR development of the novel dopamine antagonists.
Asunto(s)
Benzodiazepinas/química , Antagonistas de Dopamina/química , Neurotransmisores/química , Receptores de Dopamina D1/antagonistas & inhibidores , Benzazepinas/química , Benzazepinas/farmacología , Benzodiazepinas/síntesis química , Benzodiazepinas/farmacología , Antagonistas de Dopamina/síntesis química , Antagonistas de Dopamina/farmacología , Antagonistas de los Receptores de Dopamina D2 , Diseño de Fármacos , Humanos , Neurotransmisores/síntesis química , Neurotransmisores/farmacología , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Relación Estructura-ActividadRESUMEN
Melanin-concentrating hormone receptor 1 (MCH-R1) is a G-protein-coupled receptor (GPCR) and a target for the development of therapeutics for obesity. The structure-based development of MCH-R1 and other GPCR antagonists is hampered by the lack of an available experimentally determined atomic structure. A ligand-steered homology modeling approach has been developed (where information about existing ligands is used explicitly to shape and optimize the binding site) followed by docking-based virtual screening. Top scoring compounds identified virtually were tested experimentally in an MCH-R1 competitive binding assay, and six novel chemotypes as low micromolar affinity antagonist "hits" were identified. This success rate is more than a 10-fold improvement over random high-throughput screening, which supports our ligand-steered method. Clearly, the ligand-steered homology modeling method reduces the uncertainty of structure modeling for difficult targets like GPCRs.
Asunto(s)
Ligandos , Modelos Moleculares , Receptores de la Hormona Hipofisaria/antagonistas & inhibidores , Receptores de la Hormona Hipofisaria/química , Receptores de Somatostatina/antagonistas & inhibidores , Receptores de Somatostatina/química , Animales , Sitios de Unión , Unión Competitiva , Células CHO , Bovinos , Cricetinae , Cricetulus , Bases de Datos Factuales , Humanos , Receptores de la Hormona Hipofisaria/metabolismo , Receptores de Somatostatina/metabolismo , Rodopsina/química , Homología de Secuencia de Aminoácido , Procesos Estocásticos , Relación Estructura-Actividad , TermodinámicaRESUMEN
A series of 3,4- and 3,5-disubstituted phenyl-containing cyclobutenedione analogues were synthesized and evaluated as CXCR2 receptor antagonists. Variations in the disubstitution pattern of the phenyl ring afforded new compounds with potent CXCR2 binding affinity in the low nanomolar ranges. Moreover, two potent compounds 19 and 26 exhibited good oral pharmacokinetic profiles.
Asunto(s)
Ciclobutanos/síntesis química , Ciclobutanos/farmacología , Receptores de Interleucina-8B/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Ciclobutanos/química , Haplorrinos , Estructura Molecular , Unión Proteica , Ratas , Relación Estructura-ActividadRESUMEN
The metabolism of our prototypical thrombin receptor antagonist 1, Ki = 2.7 nM, was studied and three major metabolites (2, 4, and 5) were found. The structures of the metabolites were verified independently by synthesis. Compound 4 was shown to be a potent antagonist of the thrombin receptor with a Ki = 11 nM. Additionally, compound 4 showed a 3-fold improvement in potency with respect to 1 in an agonist-induced ex-vivo platelet aggregation assay in cynomolgus monkeys after oral administration; this activity was sustained with 60% inhibition observed at 24 h post-dose. Compound 4 was highly active in functional assays and showed excellent oral bioavailability in rats and monkeys. Compound 4 showed a superior rat enzyme induction profile relative to compound 1, allowing it to replace compound 1 as a development candidate.
Asunto(s)
Furanos/síntesis química , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Inhibidores de Agregación Plaquetaria/síntesis química , Piridinas/síntesis química , Receptores de Trombina/antagonistas & inhibidores , Animales , Disponibilidad Biológica , Sistema Enzimático del Citocromo P-450/biosíntesis , Furanos/farmacocinética , Furanos/farmacología , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Técnicas In Vitro , Macaca fascicularis , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/farmacocinética , Inhibidores de Agregación Plaquetaria/farmacología , Piridinas/farmacocinética , Piridinas/farmacología , Ensayo de Unión Radioligante , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Structurally novel thrombin receptor (protease activated receptor 1, PAR-1) antagonists based on the natural product himbacine are described. The prototypical PAR-1 antagonist 55 showed a Ki of 2.7 nM in the binding assay, making it the most potent PAR-1 antagonist reported. 55 was highly active in several functional assays, showed excellent oral bioavailability in rat and monkey models, and showed complete inhibition of agonist-induced ex vivo platelet aggregation in cynomolgus monkeys after oral administration.
Asunto(s)
Alcaloides/síntesis química , Fibrinolíticos/síntesis química , Furanos/síntesis química , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Naftalenos/síntesis química , Piperidinas/síntesis química , Piridinas/síntesis química , Receptor PAR-1/antagonistas & inhibidores , Administración Oral , Alcaloides/química , Alcaloides/farmacología , Animales , Disponibilidad Biológica , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Cromatografía Líquida de Alta Presión , Fibrinolíticos/química , Fibrinolíticos/farmacología , Furanos/química , Furanos/farmacología , Compuestos Heterocíclicos con 3 Anillos/química , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Técnicas In Vitro , Macaca fascicularis , Naftalenos/química , Naftalenos/farmacología , Piperidinas/química , Piperidinas/farmacología , Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/química , Inhibidores de Agregación Plaquetaria/farmacología , Piridinas/química , Piridinas/farmacología , Ensayo de Unión Radioligante , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Fused oxadiazines (3) were discovered as selective and orally bioavailable γ-secretase modulators (GSMs) based on the structural framework of oxadiazoline GSMs. Although structurally related, initial modifications showed that structure-activity relationships (SARs) did not translate from the oxadiazoline to the oxadiazine series. Subsequent SAR studies on modifications at the C3 and C4 positions of the fused oxadiazine core helped to identify GSMs such as compounds 8r and 8s that were highly efficacious in vitro and in vivo in a number of animal models with highly desirable physical and pharmacological properties. Further improvements of in vitro activity and selectivity were achieved by the preparation of fused morpholine oxadiazines. The shift in specificity of APP cleavage rather than a reduction in overall γ-secretase activity and the lack of changes in substrate accumulation and Notch processing as observed in the animal studies of compound 8s confirm that the oxadiazine series of compounds are potent GSMs.
RESUMEN
Cyclic hydroxyamidines were designed and validated as isosteric replacements of the amide functionality. Compounds with these structural motifs were found to be metabolically stable and to possess highly desirable pharmacokinetic profiles. These designs were applied in the identification of γ-secretase modulators leading to highly efficacious agents for reduction of central nervous system Aß(42) in various animal models.
Asunto(s)
Amidinas/síntesis química , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Oxadiazoles/síntesis química , Oxazinas/síntesis química , Amidinas/farmacocinética , Amidinas/farmacología , Péptidos beta-Amiloides/metabolismo , Animales , Encéfalo/metabolismo , Perros , Células HEK293 , Humanos , Macaca fascicularis , Masculino , Oxadiazoles/farmacocinética , Oxadiazoles/farmacología , Oxazinas/farmacocinética , Oxazinas/farmacología , Fragmentos de Péptidos/metabolismo , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A number of novel amidine containing heterocycles were designed to reproduce the unique interaction pattern, revealed by X-ray crystallography, between the BACE-1 catalytic diad and a weak NMR screening hit (3), with special attention paid to maintaining the appropriate basicity and limiting the number of H-bonding donors of these scaffolds. The iminohydantoin cores (10 and 23) were examined first and found to interact with the catalytic diad in one of two binding modes (A and B), each with the iminohydantoin core flipped 180 degrees in relation to the other. The amidine structural motif within each core forms a bidentate interaction with a different aspartic acid of the catalytic diad. Both modes reproduced a highly conserved interaction pattern between the inhibitors and the catalytic aspartates, as revealed by 3. Potent iminohydantoin BACE-1 inhibitors have been obtained, validating the molecular design as aspartyl protease catalytic site inhibitors. Brain penetrant small molecule BACE inhibitors with high ligand efficiencies have been discovered, enabling multiple strategies for further development of these inhibitors into highly potent, selective and in vivo efficacious BACE inhibitors.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Guanidinas/farmacología , Espectroscopía de Resonancia Magnética , Bibliotecas de Moléculas Pequeñas/química , Cristalografía por Rayos X , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Guanidinas/síntesis química , Guanidinas/química , Humanos , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Estudios de Validación como AsuntoRESUMEN
Fragment-based NMR screening, X-ray crystallography, structure-based design, and focused chemical library design were used to identify novel inhibitors for BACE-1. A rapid optimization of an initial NMR hit was achieved by a combination of NMR and a functional assay, resulting in the identification of an isothiourea hit with a K(d) of 15 microM for BACE-1. NMR data and the crystal structure revealed that this hit makes H-bond interactions with the two catalytic aspartates, occupies the nonprime side region of the active site of BACE-1, and extends toward the S3 subpocket (S3sp). A focused NMR-based search for heterocyclic isothiourea isosteres resulted in several distinct classes of BACE-1 active site directed compounds with improved chemical stability and physicochemical properties. The strategy for optimization of the 2-aminopyridine lead series to potent inhibitors of BACE-1 was demonstrated. The structure-based design of a cyclic acylguanidine lead series and its optimization into nanomolar BACE-1 inhibitors are the subject of the companion paper
Asunto(s)
Aminopiridinas/química , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/metabolismo , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Espectroscopía de Resonancia Magnética , Bibliotecas de Moléculas Pequeñas/química , Cristalografía por Rayos X , Humanos , Modelos Moleculares , Estructura Molecular , Espectrometría de Masa por Ionización de Electrospray , Relación Estructura-ActividadRESUMEN
The synthesis and biological activity of a novel series of thrombin receptor antagonists is described. This series of compounds showed excellent in vitro and in vivo potency. The most potent compound 40 had an IC(50) of 7.6 nM and showed robust inhibition of platelet aggregation in a cynomolgus monkey model after oral administration.
Asunto(s)
Alcaloides/farmacología , Química Farmacéutica/métodos , Furanos/farmacología , Naftalenos/farmacología , Parasimpatolíticos/farmacología , Piperidinas/farmacología , Receptores de Trombina/antagonistas & inhibidores , Administración Oral , Alcaloides/química , Animales , Área Bajo la Curva , Furanos/química , Concentración 50 Inhibidora , Ligandos , Macaca fascicularis , Modelos Químicos , Naftalenos/química , Parasimpatolíticos/química , Piperidinas/química , Agregación Plaquetaria/efectos de los fármacos , Unión Proteica , Ratas , Trombina/químicaRESUMEN
The design, synthesis, and SAR studies of a structurally novel series of highly potent thrombin receptor (PAR-1) antagonists are described. Compound 30 is a highly potent thrombin receptor antagonist (IC(50)=6.3 nM), a related compound 36 showing efficacy in a monkey ex vivo study.
Asunto(s)
Fibrinolíticos/síntesis química , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Piridinas/síntesis química , Quinolinas/química , Receptor PAR-1/antagonistas & inhibidores , Animales , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Fibrinolíticos/química , Fibrinolíticos/farmacología , Compuestos Heterocíclicos con 3 Anillos/química , Compuestos Heterocíclicos con 3 Anillos/farmacología , Macaca fascicularis , Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/química , Inhibidores de Agregación Plaquetaria/farmacología , Piridinas/química , Piridinas/farmacología , Receptores de Trombina/metabolismo , Relación Estructura-ActividadRESUMEN
The structure-activity relationship (SAR) of the lactone ring of himbacine derived thrombin receptor (PAR-1) antagonists (e.g., 2-5) is described. The effect of the lactone carbonyl group on binding to PAR-1 is dependent on the substitution pattern of the pyridine ring. A stereoselective intramolecular Michael addition reaction to the vinyl pyridine group was observed for these pyridine analogs of himbacine in basic conditions at elevated temperature.
Asunto(s)
Alcaloides/química , Furanos/química , Lactonas/química , Naftalenos/química , Piperidinas/química , Receptor PAR-1/antagonistas & inhibidores , Concentración 50 Inhibidora , Estructura Molecular , Receptor PAR-1/metabolismo , Relación Estructura-ActividadRESUMEN
A structure-activity study on benzylpiperidine 1 was accomplished by utilizing high-throughput synthesis. Three focused libraries were designed and synthesized to quickly develop SAR. Further optimization led to the discovery of compound 2, an MCH receptor R1 antagonist with over 400-fold improvement in biological activity over the original lead.