RESUMEN
The phosphoinositide 3-kinases (PI3Ks) have been linked to an extraordinarily diversified group of cellular functions making these enzymes compelling targets for the treatment of disease. A large body of evidence has linked PI3Kγ to the modulation of autoimmune and inflammatory processes making it an intriguing target for drug discovery. Our high-throughput screening (HTS) campaign revealed two hits that were nominated for further optimization studies. The in vitro activity of the first HTS hit, designated as the sulfonylpiperazine scaffold, was optimized utilizing structure-based design. However, nonoptimal pharmacokinetic properties precluded this series from further studies. An overlay of the X-ray structures of the sulfonylpiperazine scaffold and the second HTS hit within their complexes with PI3Kγ revealed a high degree of overlap. This feature was utilized to design a series of hybrid analogues including advanced leads such as 31 with desirable potency, selectivity, and oral bioavailability.
Asunto(s)
Inhibidores de las Quinasa Fosfoinosítidos-3 , Piperazinas/síntesis química , Sulfonamidas/síntesis química , Sulfonas/síntesis química , Administración Oral , Animales , Disponibilidad Biológica , Línea Celular , Cristalografía por Rayos X , Femenino , Ensayos Analíticos de Alto Rendimiento , Humanos , Isoenzimas/antagonistas & inhibidores , Mediciones Luminiscentes , Ratones , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Estructura Molecular , Fosforilación , Piperazinas/farmacocinética , Piperazinas/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Sulfonamidas/farmacocinética , Sulfonamidas/farmacología , Sulfonas/farmacocinética , Sulfonas/farmacologíaRESUMEN
CDC7 is a serine/threonine kinase that has been shown to be required for the initiation and maintenance of DNA replication. Up-regulation of CDC7 is detected in multiple tumor cell lines, with inhibition of CDC7 resulting in cell cycle arrest. In this paper, we disclose the discovery of a potent and selective CDC7 inhibitor, XL413 (14), which was advanced into Phase 1 clinical trials. Starting from advanced lead 3, described in a preceding communication, we optimized the CDC7 potency and selectivity to demonstrate in vitro CDC7 dependent cell cycle arrest and in vivo tumor growth inhibition in a Colo-205 xenograft model.
Asunto(s)
Proteínas de Ciclo Celular/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirimidinonas/química , Pirimidinonas/farmacocinética , Animales , Sitios de Unión , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Simulación por Computador , Humanos , Ratones , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Serina-Treonina Quinasas/metabolismo , Estructura Terciaria de Proteína , Pirimidinonas/uso terapéutico , Ratas , Relación Estructura-Actividad , Trasplante Heterólogo , Regulación hacia ArribaRESUMEN
A novel series of potent inhibitors of glucosylceramide synthase are described. The optimization of biochemical and cellular potency as well as ADME properties led to compound 23c. Broad tissue distribution was obtained following oral administration to mice. Thus 23c could be another useful tool compound for studying the effects of GCS inhibition in vitro and in vivo.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Glucosiltransferasas/antagonistas & inhibidores , Glucosiltransferasas/metabolismo , Administración Oral , Animales , Descubrimiento de Drogas , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacocinética , Humanos , Ratones , Ratones Endogámicos C57BL , Relación Estructura-ActividadRESUMEN
Building on our initial work, we have identified additional novel inhibitors of sphingosine kinase-1 (SK1). These new analogs address the shortcomings found in our previously reported compounds. Inhibitors 51 and 54 demonstrated oral bioavailability in a rat PK study.
Asunto(s)
Benzaldehídos/química , Inhibidores Enzimáticos/química , Litio/química , Fosfotransferasas (Aceptor de Grupo Alcohol)/antagonistas & inhibidores , Animales , Benzaldehídos/síntesis química , Benzaldehídos/farmacocinética , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Humanos , Microsomas Hepáticos/metabolismo , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , RatasRESUMEN
Sphingosine kinase 1 (SK1) is an important enzyme that regulates the balance between ceramide and sphingosine-1-phosphate (S1P). Potent and novel SK1 inhibitors (6ag, 9ab and 12aa) have been discovered through a series of modifications of sphingosine (1), the substrate of this enzyme.
Asunto(s)
Aminobutiratos/química , Inhibidores Enzimáticos/química , Homoserina/análogos & derivados , Fosfotransferasas (Aceptor de Grupo Alcohol)/antagonistas & inhibidores , Prolina/análogos & derivados , Aminobutiratos/síntesis química , Aminobutiratos/farmacología , Línea Celular Tumoral , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Homoserina/síntesis química , Homoserina/química , Homoserina/farmacología , Humanos , Lisofosfolípidos/química , Lisofosfolípidos/metabolismo , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Prolina/síntesis química , Prolina/química , Prolina/farmacología , Esfingosina/análogos & derivados , Esfingosina/química , Esfingosina/metabolismoRESUMEN
Tetracyclines and tetracycline analogues are prepared by a convergent, single-step Michael-Claisen condensation of AB precursor 1 or 2 with D-ring precursors of wide structural variability, followed by removal of protective groups (typically in two steps). A number of procedural variants of the key C-ring-forming reaction are illustrated in multiple examples. These include stepwise deprotonation of a D-ring precursor followed by addition of 1 or 2, in situ deprotonation of a D-ring precursor in mixture with 1 or 2, and in situ lithium-halogen exchange of a benzylic bromide D-ring precursor in the presence of 1 or 2, followed by warming. The AB plus D strategy for tetracycline synthesis by C-ring construction is shown to be robust across a range of different carbocyclic and heterocyclic D-ring precursors, proceeding reliably and with a high degree of stereochemical control. Evidence suggests that Michael addition of the benzylic anion derived from a given D-ring precursor to enones 1 or 2 is quite rapid at -78 degrees C, while Claisen cyclization of the enolate produced is rate-determining, typically occurring upon warming to 0 degrees C. The AB plus D coupling strategy is also shown to be useful for the construction of tetracycline precursors that are diversifiable by latter-stage transformations, subsequent to cyclization to form the C ring. Results of antibacterial assays and preliminary data obtained from a murine septicemia model show that many of the novel tetracyclines synthesized have potent antibiotic activities, both in bacterial cell culture and in vivo. The platform for tetracycline synthesis described gives access to a broad range of molecules that would be inaccessible by semisynthetic methods (presently the only means of tetracycline production) and provides a powerful engine for the discovery and, perhaps, development of new tetracycline antibiotics.
Asunto(s)
Antibacterianos/síntesis química , Tetraciclinas/síntesis química , Animales , Antibacterianos/farmacología , Bacteriemia/tratamiento farmacológico , Cristalografía por Rayos X , Ciclización , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus/efectos de los fármacos , Tetraciclinas/farmacologíaRESUMEN
[reaction: see text] Several aryl ketone precursors useful in the synthesis of known physiologically active compounds have been reduced to the corresponding nonracemic alcohols. The previously reported combination of a catalytic quantity of (R)-(-)-DTBM-SEGPHOS-ligated CuH and stoichiometric PMHS is shown to be very effective in these asymmetric hydrosilylations.
RESUMEN
When complexed by selected ligands in either the BIPHEP or the SEGPHOS series, CuH is an extremely reactive catalyst capable of effecting asymmetric hydrosilylations of aromatic ketones at temperatures between -50 and -78 degrees C. Inexpensive silanes serve as stoichiometric sources of hydride. Substrate-to-ligand ratios exceeding 100000:1 have been documented. The level of induction is usually in the >90% ee category. The nature of the reagent has been investigated using spectroscopic and chemical means, although its composition remains unclear.
RESUMEN
In situ generation of CuH ligated by Takasago's new nonracemic ligand, DTBM-SEGPHOS, leads to an especially reactive reagent capable of effecting asymmetric hydrosilylation of heteroaromatic (H) ketones under very mild conditions. PMHS serves as an inexpensive source of hydride. Substrate-to-ligand ratios on the order of 2000:1 are employed. [reaction: see text]