RESUMEN
We have identified two related series of dibenzazepine and dibenzoxazepine sodium channel blockers, which showed good potency on Nav1.7 in FLIPR-based and electrophysiological functional assays.
Asunto(s)
Dibenzazepinas/química , Dibenzoxazepinas/química , Canal de Sodio Activado por Voltaje NAV1.7/fisiología , Bloqueadores de los Canales de Sodio/química , Animales , Dibenzazepinas/farmacología , Dibenzoxazepinas/farmacología , Humanos , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/fisiología , Ratas , Bloqueadores de los Canales de Sodio/farmacologíaRESUMEN
We have identified a new series of N-aryl azacycles as sodium channel blockers, which showed good potency on Nav1.7 in FLIPR-based and electrophysiological functional assays. Analogs from this series possessed selectivity over hERG, reasonable oral exposure in rat PK studies and are predicted to have limited CNS penetration.
Asunto(s)
Canal de Sodio Activado por Voltaje NAV1.7/fisiología , Bloqueadores de los Canales de Sodio/síntesis química , Secuencia de Aminoácidos , Animales , Permeabilidad de la Membrana Celular/efectos de los fármacos , Permeabilidad de la Membrana Celular/fisiología , Perros , Células de Riñón Canino Madin Darby , Datos de Secuencia Molecular , Ratas , Bloqueadores de los Canales de Sodio/farmacologíaRESUMEN
We report the discovery of a novel series of ATP-competitive Janus kinase 3 (JAK3) inhibitors based on the 5H-pyrrolo[2,3-b]pyrazine scaffold. The initial leads in this series, compounds 1a and 1h, showed promising potencies, but a lack of selectivity against other isoforms in the JAK family. Computational and crystallographic analysis suggested that the phenyl ether moiety possessed a favorable vector to achieve selectivity. Exploration of this vector resulted in the identification of 12b and 12d, as potent JAK3 inhibitors, demonstrating improved JAK family and kinase selectivity.
Asunto(s)
Janus Quinasa 3/antagonistas & inhibidores , Éteres Fenílicos/química , Inhibidores de Proteínas Quinasas/química , Piridazinas/química , Pirroles/química , Sitios de Unión , Dominio Catalítico , Evaluación Preclínica de Medicamentos , Janus Quinasa 3/metabolismo , Simulación del Acoplamiento Molecular , Éteres Fenílicos/síntesis química , Éteres Fenílicos/metabolismo , Unión Proteica , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/metabolismo , Relación Estructura-ActividadRESUMEN
Using a structure based design approach we have identified a series of indazole substituted pyrrolopyrazines, which are potent inhibitors of JAK3. Intramolecular electronic repulsion was used as a strategy to induce a strong conformational bias within the ligand. Compounds bearing this conformation participated in a favorable hydrophobic interaction with a cysteine residue in the JAK3 binding pocket, which imparted high selectivity versus the kinome and improved selectivity within the JAK family.
Asunto(s)
Diseño de Fármacos , Janus Quinasa 3/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Sitios de Unión , Cristalografía por Rayos X , Interacciones Hidrofóbicas e Hidrofílicas , Indazoles/química , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 1/metabolismo , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 2/metabolismo , Janus Quinasa 3/metabolismo , Simulación del Acoplamiento Molecular , Unión Proteica , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/metabolismo , Estructura Terciaria de Proteína , Pirazinas/síntesis química , Pirazinas/química , Pirazinas/metabolismo , Relación Estructura-ActividadRESUMEN
We describe the discovery of several pyrrolopyrazines as potent and selective Syk inhibitors and the efforts that eventually led to the desired improvements in physicochemical properties and human whole blood potencies. Ultimately, our mouse model revealed unexpected toxicity that precluded us from further advancing this series.
Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirazinas/síntesis química , Pirroles/síntesis química , Animales , Linfocitos B/efectos de los fármacos , Linfocitos B/enzimología , Proteínas Sanguíneas/metabolismo , Cristalografía por Rayos X , Humanos , Ratones , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Estructura Molecular , Unión Proteica , Pirazinas/farmacología , Pirazinas/toxicidad , Pirroles/farmacología , Pirroles/toxicidad , Relación Estructura-Actividad , Quinasa SykRESUMEN
Two new series of monoamine triple reuptake inhibitors (TRIs) have been discovered through scaffold homologation of our recently reported series of 3,3-disubstituted pyrrolidine TRIs. The regioisomeric 2- and 3-ketopyrrolidines demonstrated high levels of potency against all three monoamine transporters as well as good human in vitro stability, low drug-drug interaction potential and a decreased propensity for hERG channel binding. Representative compounds from these series displayed good in vivo pharmacokinetics and high monoamine receptor occupancies which are indicators of good brain penetration.
Asunto(s)
Antidepresivos Tricíclicos/farmacología , Dopamina/metabolismo , Inhibidores de la Captación de Neurotransmisores/farmacología , Norepinefrina/metabolismo , Pirrolidinas/farmacología , Serotonina/metabolismo , Animales , Antidepresivos Tricíclicos/síntesis química , Antidepresivos Tricíclicos/química , Antidepresivos Tricíclicos/farmacocinética , Células CACO-2 , Depresión/tratamiento farmacológico , Inhibidores de Captación de Dopamina/síntesis química , Inhibidores de Captación de Dopamina/química , Inhibidores de Captación de Dopamina/farmacocinética , Inhibidores de Captación de Dopamina/farmacología , Diseño de Fármacos , Humanos , Inhibidores de la Captación de Neurotransmisores/síntesis química , Inhibidores de la Captación de Neurotransmisores/química , Inhibidores de la Captación de Neurotransmisores/farmacocinética , Dolor/tratamiento farmacológico , Pirrolidinas/síntesis química , Pirrolidinas/química , Pirrolidinas/farmacocinética , Ratas , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Inhibidores Selectivos de la Recaptación de Serotonina/farmacologíaRESUMEN
A series of 3,3-disubstituted pyrrolidine monoamine triple reuptake inhibitors were discovered. Analogues with low nanomolar potency, good human in vitro microsomal stability and in vitro permeability, and low drug-drug interaction potential are described. One example showed in vivo anti-depressant-like effects in the mouse tail suspension assay with a minimum effective dose of 30 mg/kg i.p.
Asunto(s)
Inhibidores de Captación de Dopamina/síntesis química , Inhibidores de Captación de Dopamina/farmacología , Pirrolidinas/síntesis química , Pirrolidinas/farmacología , Animales , Antidepresivos/farmacología , Inhibidores de Captación de Dopamina/química , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Humanos , Ratones , Estructura Molecular , Actividad Motora/efectos de los fármacos , Norepinefrina/metabolismo , Pirrolidinas/química , Serotonina/metabolismo , Cola (estructura animal)/efectos de los fármacosRESUMEN
The cytosolic thioredoxin redox system composed of thioredoxin-1 and the NADPH-dependent thioredoxin reductase-1 reductase is an important regulator of cell growth and survival. Thioredoxin-1 is overexpressed in many human tumors where it is associated with increased cell proliferation, decreased apoptosis, and decreased patient survival. We hypothesized that thioredoxin reductase-1 provides a target to inhibit the activity of overexpressed thioredoxin-1 for the development of novel anticancer agents. We found that the naphthoquinone spiroketal fungal metabolite palmarumycin CP1 is a potent inhibitor of thioredoxin reductase-1, but attempts to exploit the activity of palmarumycin CP1 analogues as antitumor agents in vivo were hampered by their insolubility. We have therefore developed PX-916, a water-soluble prodrug of a palmarumycin CP1 analogue. PX-916 rapidly releases the parent compound at physiologic pH and in plasma but is stable at acid pH, allowing its i.v. administration. PX-916 is a potent inhibitor of purified human thioredoxin reductase-1 and of thioredoxin reductase-1 activity in cells and tumor xenografts when given to mice and inhibits the downstream targets of thioredoxin-1 signaling, hypoxia-inducible factor-1alpha, and vascular endothelial growth factor in tumors. PX-916 showed excellent antitumor activity against several animal tumor models with some cures. Thus, the study shows that water-soluble inhibitors of thioredoxin reductase-1, such as PX-916, can block thioredoxin-1 signaling in tumors producing marked inhibition of tumor growth.
Asunto(s)
Antineoplásicos/farmacología , Dioxanos/química , Dioxanos/farmacología , Inhibidores Enzimáticos/farmacología , Glicina/análogos & derivados , Neoplasias/enzimología , Compuestos de Espiro/química , Reductasa de Tiorredoxina-Disulfuro/antagonistas & inhibidores , Animales , Línea Celular Tumoral , Dioxanos/farmacocinética , Glicina/química , Glicina/farmacocinética , Glicina/farmacología , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Ratones , Naftalenos , Compuestos de Espiro/farmacología , Tiorredoxina Reductasa 1 , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A series of palmarumycin prodrugs and water-soluble analogs has been synthesized and assayed for inhibition of the thioredoxin-thioredoxin reductase system. Increased aqueous solubility led to an improved in vivo activity profile.
Asunto(s)
Antineoplásicos/síntesis química , Profármacos/síntesis química , Reductasa de Tiorredoxina-Disulfuro/antagonistas & inhibidores , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Naftalenos/química , Naftalenos/farmacología , Profármacos/farmacología , Solubilidad , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Relación Estructura-Actividad , Tiorredoxinas/antagonistas & inhibidoresRESUMEN
[reaction: see text] The intramolecular Diels-Alder cycloaddition reaction (IMDAF) of several N-phenylsulfonylindolyl-substituted furanyl carbamates containing a tethered pi-bond on the indole ring were examined as an approach to the iboga alkaloid catharanthine. Only in the case where the tethered pi-bond contained two carbomethoxy groups did the [4 + 2]-cycloaddition occur. Push-pull dipoles generated from the Rh(II)-catalyzed reaction of diazo imides, on the other hand, undergo successful intramolecular 1,3-dipolar cycloaddition across both alkenyl and heteroaromatic pi-bonds to provide novel pentacyclic compounds in good yield and in a stereocontrolled fashion. The facility of the cycloaddition was found to be critically dependent on conformational factors in the transition state. Ligand substitution in the rhodium(II) catalyst markedly altered the product ratio between [3 + 2]-cycloaddition and intramolecular C-H insertion. The variation in reactivity reflects the difference in electrophilicity between the various rhodium carbenoid intermediates. Intramolecular C-H insertion is enhanced with the more electrophilic carbene generated using Rh(II) perfluorobutyrate.
Asunto(s)
Compuestos Heterocíclicos/química , Indoles/síntesis química , Catálisis , Ciclización , Compuestos Heterocíclicos/síntesis química , Imidas/química , Conformación Molecular , Rodio/química , EstereoisomerismoRESUMEN
Spiroketal naphthodecalins are readily assembled by Barton's base mediated Ullmann binaphthyl ether coupling, Dakin reactions and hypervalent iodine spirocyclization. The core structures can be further diversified by enone addition and Stille coupling reactions. Nanomolar inhibitors for the Trx/TrxR redox control system were prepared by this approach and compared to series of natural product isolates. Cytotoxicity in MCF-7 cell assays ranged from an IC50 of 1.6 to >100 microM.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Reductasa de Tiorredoxina-Disulfuro/antagonistas & inhibidores , Tiorredoxinas/antagonistas & inhibidores , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/química , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Naftoquinonas/química , Naftoquinonas/farmacología , Compuestos de Espiro/química , Compuestos de Espiro/farmacologíaRESUMEN
The intramolecular Diels-Alder reaction between an amidofuran moiety tethered onto an indole component was examined as a strategy for the synthesis of Aspidosperma alkaloids. Furanyl carbamate 23 was acylated using the mixed anhydride 26 to provide amidofuran 22 in 68% yield. Further N-acylation of this indole furnished 27 in 88% yield. Cyclization precursors were prepared by removing the carbamate moiety followed by N-alkylation with the appropriate alkyl halides. Large substituent groups on the amido nitrogen atom causes the reactive s-trans conformation of the amidofuran to be more highly populated, thereby facilitating the Diels-Alder cycloaddition. The reaction requires the presence of an electron-withdrawing substituent on the indole nitrogen in order for the cycloaddition to proceed. Treatment of N-allyl-bromoenamide 48 with n-Bu(3)SnH/AIBN preferentially led to the 6-endo trig cyclization product 50, with the best yield (91%) being obtained under high dilution conditions. The initially generated cyclohexenyl radical derived from 48 produces the pentacyclic heterocycle 50 by either a direct 6-endo trig cyclization or, alternatively, by a vinyl radical rearrangement pathway.
Asunto(s)
Alcaloides/química , Indoles/química , Alcaloides/síntesis química , Aspidosperma/química , Ciclización , Estructura MolecularRESUMEN
[reaction: see text] Electron-rich dinaphthyl ethers were synthesized by S(N)Ar reactions between naphthols and activated fluoronaphthalenes. 2-tert-Butyl-1,1,3,3-tetramethylguanidine (Barton's base) was found to be an excellent, mild alternative to traditional inorganic bases for promoting the coupling reaction.
Asunto(s)
Éteres/química , Éteres/síntesis química , Guanidina/química , Naftoles/química , Oxígeno/química , Guanidina/análogos & derivados , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Estructura Molecular , Naftalenos/química , Compuestos de EspiroRESUMEN
[reaction: see text] The intramolecular Diels-Alder reaction between an amidofuran moiety tethered onto an indole component was examined as a strategy for the synthesis of Aspidosperma and Strychnos alkaloids. Furanyl carbamate 13 was acylated using the mixed anhydride 16 to provide amidofuran 12 in 68% yield. Further N-acylation of this indole furnished 17 in 88% yield. Cyclization precursors were prepared by removing the carbamate moiety followed by N-alkylation with the appropriate alkyl halides. Thermolysis of 25 provided the novel tetracyclic ketone 26 in 74% yield.
Asunto(s)
Alcaloides/síntesis química , Aspidosperma/química , Strychnos/química , Ciclización , Indoles/químicaRESUMEN
A series of 2-(methylthio)-5-amidofurans containing tethered unsaturation were prepared via the reaction of dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF) with beta-alkoxy-gamma-dithiane amides 13-16 and 27-32 in 40-70% yield. Thermolysis of these furans resulted in an intramolecular Diels-Alder reaction (IMDAF). With the exception of 45 and 46, the oxa-bridged cycloadducts could not be isolated but immediately underwent a 1,2-methylthio shift to form bicyclic lactams in 60-100% yield. It was determined that incorporation of the amido carbonyl in the tether allowed the IMDAF reaction to proceed at a lower temperature. A dramatic example of this is seen in the IMDAF reaction of furan 35, in which the presence of an amido carbonyl as part of the dienophile tether, as opposed to the annealed ring (66) or the lack of a carbonyl (67), was necessary for the cycloaddition to occur. Furan 37, annealed to an azepine ring, underwent the IMDAF reaction at or below room temperature. To identify structural features that promote the IMDAF reaction, a computational study was undertaken. Ground-state and transition-state energies were calculated for furans 17, 33, 37, and 64 using the Becke 3LYP/6-31G model. The theoretical results were in good agreement with those observed. The results indicate that the incorporation of an amide carbonyl as part of the tether system works to place the dienophile in closer proximity to the furan ring, thereby lowering the activation energy needed to reach the transition state.
Asunto(s)
Amidas/química , Furanos/química , Furanos/síntesis química , Hidrocarburos Policíclicos Aromáticos/química , Hidrocarburos Policíclicos Aromáticos/síntesis química , Catálisis , Cristalografía por Rayos X , Ciclización , Espectrometría de Masas , Modelos Moleculares , Conformación Molecular , Estructura Molecular , TemperaturaRESUMEN
[reaction: see text] Various factors that influence the rate of the intramolecular Diels-Alder reaction of amidofurans were investigated with density functional theory calculations using the Becke3LYP/6-31G* model. Conformational effects imposed by the placement of a carbonyl group within the tether, combined with a rotational bias about the C(2)-N bond, account for the observed rate differences in the thermal chemistry of these amidofurans.