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1.
Genes Cells ; 26(5): 298-312, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33608942

RESUMEN

In eukaryotic nuclei, a number of phase-separated nuclear bodies (NBs) are present. RNA polymerase II (Pol II) is the main player in transcription and forms large condensates in addition to localizing at numerous transcription foci. Cajal bodies (CBs) and histone locus bodies (HLBs) are NBs that are involved in transcriptional and post-transcriptional regulation of small nuclear RNA and histone genes. By live-cell imaging using human HCT116 cells, we here show that Pol II condensates (PCs) nucleated near CBs and HLBs, and the number of PCs increased during S phase concomitantly with the activation period of histone genes. Ternary PC-CB-HLB associates were formed via three pathways: nucleation of PCs and HLBs near CBs, interaction between preformed PC-HLBs with CBs and nucleation of PCs near preformed CB-HLBs. Coilin knockout increased the co-localization rate between PCs and HLBs, whereas the number, nucleation timing and phosphorylation status of PCs remained unchanged. Depletion of PCs did not affect CBs and HLBs. Treatment with 1,6-hexanediol revealed that PCs were more liquid-like than CBs and HLBs. Thus, PCs are dynamic structures often nucleated following the activation of gene clusters associated with other NBs.


Asunto(s)
Cuerpos Enrollados/metabolismo , Histonas/metabolismo , ARN Polimerasa II/metabolismo , Supervivencia Celular/efectos de los fármacos , Cuerpos Enrollados/efectos de los fármacos , Glicoles/farmacología , Proteínas Fluorescentes Verdes/metabolismo , Células HCT116 , Humanos , Modelos Biológicos , Proteínas Nucleares/metabolismo , Fase S/efectos de los fármacos
2.
J Med Chem ; 63(3): 1084-1104, 2020 02 13.
Artículo en Inglés | MEDLINE | ID: mdl-31895562

RESUMEN

In our pursuit of developing a novel, potent, and selective cell division cycle 7 (Cdc7) inhibitor, we optimized the previously reported thieno[3,2-d]pyrimidinone analogue I showing time-dependent Cdc7 kinase inhibition and slow dissociation kinetics. These medicinal chemistry efforts led to the identification of compound 3d, which exhibited potent cellular activity, excellent kinase selectivity, and antitumor efficacy in a COLO205 xenograft mouse model. However, the issue of formaldehyde adduct formation emerged during a detailed study of 3d, which was deemed an obstacle to further development. A structure-based approach to circumvent the adduct formation culminated in the discovery of compound 11b (TAK-931) possessing a quinuclidine moiety as a preclinical candidate. In this paper, the design, synthesis, and biological evaluation of this series of compounds will be presented.


Asunto(s)
Antineoplásicos/uso terapéutico , Proteínas de Ciclo Celular/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirazolonas/uso terapéutico , Pirimidinas/uso terapéutico , Pirimidinonas/uso terapéutico , Quinuclidinas/uso terapéutico , Tiofenos/uso terapéutico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Sitios de Unión , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Diseño de Fármacos , Descubrimiento de Drogas , Formaldehído/química , Humanos , Ratones , Simulación del Acoplamiento Molecular , Estructura Molecular , Unión Proteica , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo , Pirazolonas/farmacología , Pirimidinas/farmacología , Pirimidinonas/síntesis química , Pirimidinonas/metabolismo , Quinuclidinas/síntesis química , Quinuclidinas/metabolismo , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
3.
Sci Adv ; 5(5): eaav3660, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-31131319

RESUMEN

Replication stress (RS) is a cancer hallmark; chemotherapeutic drugs targeting RS are widely used as treatments for various cancers. To develop next-generation RS-inducing anticancer drugs, cell division cycle 7 (CDC7) has recently attracted attention as a target. We have developed an oral CDC7-selective inhibitor, TAK-931, as a candidate clinical anticancer drug. TAK-931 induced S phase delay and RS. TAK-931-induced RS caused mitotic aberrations through centrosome dysregulation and chromosome missegregation, resulting in irreversible antiproliferative effects in cancer cells. TAK-931 exhibited significant antiproliferative activity in preclinical animal models. Furthermore, in indication-seeking studies using large-scale cell panel data, TAK-931 exhibited higher antiproliferative activities in RAS-mutant versus RAS-wild-type cells; this finding was confirmed in pancreatic patient-derived xenografts. Comparison analysis of cell panel data also demonstrated a unique efficacy spectrum for TAK-931 compared with currently used chemotherapeutic drugs. Our findings help to elucidate the molecular mechanisms for TAK-931 and identify potential target indications.


Asunto(s)
Antineoplásicos/farmacología , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirazolonas/farmacología , Pirimidinas/farmacología , Animales , Línea Celular Tumoral , Proliferación Celular , Separación Celular , Supervivencia Celular , Centrosoma/efectos de los fármacos , Aberraciones Cromosómicas/efectos de los fármacos , Biología Computacional , Resistencia a Antineoplásicos/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Células HeLa , Humanos , Concentración 50 Inhibidora , Estimación de Kaplan-Meier , Ratones , Ratones Endogámicos BALB C , Mitosis/efectos de los fármacos , Modelos Animales , Mutación , Trasplante de Neoplasias , Neoplasias Pancreáticas/tratamiento farmacológico , Unión Proteica , Inhibidores de Proteínas Quinasas/farmacología , Proteómica , Resultado del Tratamiento , Ensayos Antitumor por Modelo de Xenoinjerto
4.
J Med Chem ; 62(3): 1167-1179, 2019 02 14.
Artículo en Inglés | MEDLINE | ID: mdl-30652849

RESUMEN

Retinoic acid receptor-related orphan receptor γt (RORγt) agonists are expected to provide a novel class of immune-activating anticancer drugs via activation of Th17 cells and Tc17 cells. Herein, we describe a novel structure-based functionality switching approach from in house well-optimized RORγt inverse agonists to potent RORγt agonists. We succeeded in the identification of potent RORγt agonist 5 without major chemical structure change. The biochemical response was validated by molecular dynamics simulation studies that showed a helix 12 stabilization effect of RORγt agonists. These results indicate that targeting helix 12 is an attractive and novel medicinal chemistry strategy for switching existing RORγt inverse agonists to agonists.


Asunto(s)
Diseño de Fármacos , Agonismo Inverso de Drogas , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Animales , Ensayos Analíticos de Alto Rendimiento , Simulación de Dinámica Molecular , Relación Estructura-Actividad , Células Th17/efectos de los fármacos
5.
ACS Synth Biol ; 7(11): 2537-2546, 2018 11 16.
Artículo en Inglés | MEDLINE | ID: mdl-30277749

RESUMEN

Although conjugation with polyethylene glycol (PEGylation) improves the pharmacokinetics of therapeutic proteins, it drastically decreases their bioactivity. Site-specific PEGylation counters the reduction in bioactivity, but developing PEGylated proteins with equivalent bioactivity to that of their unmodified counterparts remains challenging. This study aimed to generate PEGylated proteins with equivalent bioactivity to that of unmodified counterparts. Using interferon (IFN) as a model protein, a highly bioactive Lys-deficient protein variant generated using our unique directed evolution methods enables the design of a site-specific di-PEGylated protein. Antiviral activity of our di-PEGylated IFN was similar to that of unmodified IFN-α2b. The di-PEGylated IFN exhibited 3.0-fold greater antiviral activity than that of a commercial PEGylated IFN. Moreover, our di-PEGylated IFN showed higher in vitro and in vivo stability than those of unmodified IFN-α2b. Hence, we propose that highly bioactive Lys-deficient proteins solve the limitation of conventional PEGylation with respect to the reduction in bioactivity of PEGylated proteins.


Asunto(s)
Interferón-alfa/metabolismo , Polietilenglicoles/química , Animales , Antivirales/sangre , Antivirales/química , Antivirales/metabolismo , Evolución Molecular Dirigida , Humanos , Interferón alfa-2 , Interferón-alfa/química , Interferón-alfa/genética , Lisina/deficiencia , Ratones , Mutagénesis Sitio-Dirigida , Estabilidad Proteica , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/sangre , Proteínas Recombinantes/genética
6.
J Med Chem ; 61(7): 2973-2988, 2018 04 12.
Artículo en Inglés | MEDLINE | ID: mdl-29510038

RESUMEN

A series of tetrahydronaphthyridine derivatives as novel RORγt inverse agonists were designed and synthesized. We reduced the lipophilicity of tetrahydroisoquinoline compound 1 by replacement of the trimethylsilyl group and SBDD-guided scaffold exchange, which successfully afforded compound 7 with a lower log  D value and tolerable in vitro activity. Consideration of LLE values in the subsequent optimization of the carboxylate tether led to the discovery of [ cis-3-({(5 R)-5-[(7-fluoro-1,1-dimethyl-2,3-dihydro-1 H-inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5 H)-yl}carbonyl)cyclobutyl]acetic acid, TAK-828F (10), which showed potent RORγt inverse agonistic activity, excellent selectivity against other ROR isoforms and nuclear receptors, and a good pharmacokinetic profile. In animal studies, oral administration of compound 10 exhibited robust and dose-dependent inhibition of IL-17A cytokine expression in a mouse IL23-induced gene expression assay. Furthermore, development of clinical symptoms in a mouse experimental autoimmune encephalomyelitis model was significantly reduced. Compound 10 was selected as a clinical compound for the treatment of Th17-driven autoimmune diseases.


Asunto(s)
Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Receptores de Ácido Retinoico/agonistas , Animales , Enfermedades Autoinmunes/tratamiento farmacológico , Descubrimiento de Drogas , Agonismo Inverso de Drogas , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Expresión Génica/efectos de los fármacos , Genes Reporteros/efectos de los fármacos , Interleucina-17/genética , Interleucina-17/metabolismo , Subunidad p19 de la Interleucina-23/genética , Subunidad p19 de la Interleucina-23/metabolismo , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Células Th17/inmunología
7.
Bioorg Med Chem ; 26(2): 470-482, 2018 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-29258712

RESUMEN

A series of tetrahydroisoquinoline derivatives were designed, synthesized, and evaluated for their potential as novel orally efficacious retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists for the treatment of Th17-driven autoimmune diseases. We carried out cyclization of the phenylglycinamide core by structure-based drug design and successfully identified a tetrahydroisoquinoline carboxylic acid derivative 14 with good biochemical binding and cellular reporter activity. Interestingly, the combination of a carboxylic acid tether and a central fused bicyclic ring was crucial for optimizing PK properties, and the compound 14 showed significantly improved PK profile. Successive optimization of the carboxylate tether led to the discovery of compound 15 with increased inverse agonistic activity and an excellent PK profile. Oral treatment of mice with compound 15 robustly and dose-dependently inhibited IL-17A production in an IL23-induced gene expression assay.


Asunto(s)
Descubrimiento de Drogas , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Tetrahidroisoquinolinas/farmacología , Administración Oral , Animales , Cristalografía por Rayos X , Citocinas/biosíntesis , Relación Dosis-Respuesta a Droga , Humanos , Inyecciones Intradérmicas , Interleucina-23/administración & dosificación , Interleucina-23/farmacología , Células Jurkat , Masculino , Ratones , Ratones Endogámicos BALB C , Modelos Animales , Modelos Moleculares , Estructura Molecular , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Relación Estructura-Actividad , Tetrahidroisoquinolinas/administración & dosificación , Tetrahidroisoquinolinas/química
8.
Nucleosides Nucleotides Nucleic Acids ; 36(6): 428-434, 2017 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-28486036

RESUMEN

Pinpoint sequence alteration (genome editing) by the combination of the site-specific cleavage of a target DNA and a donor nucleic acid has attracted much attention and the sequence of the target DNA is expected to be changed to that of a donor nucleic acid. In most cases, oligodeoxyribonucleotides (ODNs) and plasmid DNAs have been used as donors. However, a several hundred-base single-stranded (ss) DNA fragment and a 5'-tailed duplex (TD) accomplished the desired sequence changes without DNA cleavage, and might serve as better donors for the cleaved target DNA than ODNs and plasmid DNAs. In this study, sequence conversion efficiencies were compared with various donor DNAs in model sequence alteration experiments, using episomal DNA. The efficiencies with the ss and TD fragments were higher than those with the ODN and plasmid DNA. The sequence change by the TD seemed somewhat less efficient but slightly more accurate than that by the ss DNA fragment. These results suggested that the ss and TD fragments are better donors for targeted sequence alteration.


Asunto(s)
División del ADN , ADN de Cadena Simple/química , ADN de Cadena Simple/genética , Secuencia de Bases
9.
Bioorg Med Chem Lett ; 27(9): 1897-1901, 2017 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-28363748

RESUMEN

We recently reported a class of novel tissue-selective androgen receptor modulators (SARMs), represented by a naphthalene derivative A. However, their pharmacokinetic (PK) profiles were poor due to low metabolic stability. To improve the PK profiles, we modified the hydroxypyrrolidine and benzonitrile substituents of 4-(pyrrolidin-1-yl)benzonitrile derivative B, which had a comparable potency as that of compound A. This optimization led us to further modifications, which improved metabolic stability while maintaining potent androgen agonistic activity. Among the synthesized compounds, (2S,3S)-2,3-dimethyl-3-hydroxylpyrrolidine derivative 1c exhibited a suitable PK profile and improved metabolic stability. Compound 1c demonstrated significant efficacy in levator ani muscle without increasing the weight of the prostate in an in vivo study. In addition, compound 1c showed agonistic activity in the CNS, which was detected using sexual behavior induction assay.


Asunto(s)
Andrógenos/química , Andrógenos/farmacología , Nitrilos/química , Nitrilos/farmacología , Pirrolidinas/química , Pirrolidinas/farmacología , Receptores Androgénicos/metabolismo , Anabolizantes/química , Anabolizantes/farmacocinética , Anabolizantes/farmacología , Andrógenos/farmacocinética , Animales , Eunuquismo/tratamiento farmacológico , Eunuquismo/metabolismo , Humanos , Masculino , Modelos Moleculares , Músculos/efectos de los fármacos , Músculos/metabolismo , Nitrilos/farmacocinética , Tamaño de los Órganos/efectos de los fármacos , Próstata/efectos de los fármacos , Próstata/metabolismo , Pirrolidinas/farmacocinética , Ratas
10.
Biol Pharm Bull ; 39(8): 1392-5, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27476948

RESUMEN

Base sequence conversion in target DNA is achieved when a 5'-tailed duplex (TD) is introduced into cells. In this study, the effects of target DNA cleavage on sequence conversion with a TD were examined. Plasmid DNAs with and without cleavage near the target position were each introduced into HeLa cells, together with the TD. The cleavage promoted the sequence alteration efficiency by ca. 7-fold. These results suggested that the sequence conversion efficiency with the TD fragment is increased when an artificial nuclease introduces cleavage near the target site.


Asunto(s)
Secuencia de Bases , División del ADN , ADN/metabolismo , Células HeLa , Humanos , Plásmidos
11.
Bioorg Med Chem ; 21(17): 5488-502, 2013 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-23816042

RESUMEN

Centromere-associated protein-E (CENP-E), a mitotic kinesin that plays an important role in mitotic progression, is an attractive target for cancer therapeutic drugs. For the purpose of developing novel CENP-E inhibitors as cancer therapeutics, we investigated a fused bicyclic compound identified by high throughput screening, 4-oxo-4,5-dihydrothieno[3,4-c]pyridine-6-carboxamide 1a. Based on this scaffold, we designed inhibitors for efficient binding at the L5 site in CENP-E utilizing homology modeling as well as electrostatic potential map (EPM) analysis to enhance CENP-E inhibitory activity. This resulted in a new lead, 5-bromoimidazo[1,2-a]pyridine 7, which showed potent CENP-E enzyme inhibition (IC50: 50nM) and cellular activity with accumulation of phosphorylated histone H3 in HeLa cells. Our homology model and EPM analysis proved to be useful tools for the rational design of CENP-E inhibitors.


Asunto(s)
Amidas/síntesis química , Compuestos Bicíclicos con Puentes/química , Proteínas Cromosómicas no Histona/antagonistas & inhibidores , Imidazoles/síntesis química , Piridinas/síntesis química , Amidas/química , Amidas/metabolismo , Sitios de Unión , Proteínas Cromosómicas no Histona/metabolismo , Células HeLa , Histonas/metabolismo , Humanos , Imidazoles/química , Imidazoles/metabolismo , Simulación del Acoplamiento Molecular , Unión Proteica , Estructura Terciaria de Proteína , Piridinas/química , Piridinas/metabolismo , Electricidad Estática , Relación Estructura-Actividad
12.
Bioorg Med Chem ; 20(18): 5600-15, 2012 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-22883026

RESUMEN

Our aim was to discover RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors that possess strong activity and sufficient oral absorption, and thus, we selected a 5-amino-linked thiazolo[5,4-d]pyrimidine derivative as the lead compound because of its potential kinase inhibitory activities and its desired solubility. The novel tertiary 1-cyano-1-methylethoxy substituent was designed to occupy the hydrophobic region of 'back pocket' of BRAF on the basis of the X-ray co-crystal structure data of BRAF. In addition, we found that N-methylation of the amine linker could control the twisted molecular conformation leading to improved solubility. These approaches produced N-methyl thiazolo[5,4-b]pyridine-5-amine derivative 5. To maximize the in vivo efficacy, we attempted salt formation of 5. Our result indicated that the besylate monohydrate salt form (5c) showed significant improvement of both solubility and oral absorption. Owing to the improved physicochemical properties, compound 5c demonstrated regressive antitumor efficacy in a HT-29 xenograft model.


Asunto(s)
Antineoplásicos/farmacología , Diseño de Fármacos , Neoplasias Experimentales/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Tiazoles/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Células HT29 , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Ratones , Microsomas/efectos de los fármacos , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/química , Ratas , Ratas Endogámicas F344 , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/química , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
13.
Bioorg Med Chem ; 20(15): 4680-92, 2012 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-22763369

RESUMEN

As an alternative to the previously reported solid dispersion formulation for enhancing the oral absorption of thiazolo[5,4-b]pyridine 1, we investigated novel N-acyl imide prodrugs of 1 as RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors. Introducing N-acyl promoieties at the benzanilide position gave chemically stable imides. N-tert-Butoxycarbonyl (Boc) introduced imide 6 was a promising prodrug, which was converted to the active compound 1 after its oral administration in mice. Cocrystals of 6 with AcOH (6b) possessed good physicochemical properties with moderate thermodynamic solubility (19µg/mL). This crystalline prodrug 6b was rapidly and enzymatically converted into 1 after its oral absorption in mice, rats, dogs, and monkeys. Prodrug 6b showed in vivo antitumor regressive efficacy (T/C=-6.4%) in an A375 melanoma xenograft model in rats. Hence, we selected 6b as a promising candidate and are performing further studies. Herein, we report the design, synthesis, and characterization of novel imide-type prodrugs.


Asunto(s)
Antineoplásicos/farmacología , Diseño de Fármacos , Imidas/farmacología , Profármacos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/síntesis química , Línea Celular Tumoral , Cristalografía por Rayos X , Perros , Relación Dosis-Respuesta a Droga , Femenino , Haplorrinos , Humanos , Imidas/administración & dosificación , Imidas/síntesis química , Ratones , Modelos Moleculares , Estructura Molecular , Profármacos/administración & dosificación , Profármacos/síntesis química , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/síntesis química , Ratas , Ratas Desnudas , Solubilidad , Relación Estructura-Actividad , Termodinámica , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
14.
J Med Chem ; 55(7): 3452-78, 2012 Apr 12.
Artículo en Inglés | MEDLINE | ID: mdl-22376051

RESUMEN

To develop RAF/VEGFR2 inhibitors that bind to the inactive DFG-out conformation, we conducted structure-based drug design using the X-ray cocrystal structures of BRAF, starting from an imidazo[1,2-b]pyridazine derivative. We designed various [5,6]-fused bicyclic scaffolds (ring A, 1-6) possessing an anilide group that forms two hydrogen bond interactions with Cys532. Stabilizing the planarity of this anilide and the nitrogen atom on the six-membered ring of the scaffold was critical for enhancing BRAF inhibition. The selected [1,3]thiazolo[5,4-b]pyridine derivative 6d showed potent inhibitory activity in both BRAF and VEGFR2. Solid dispersion formulation of 6d (6d-SD) maximized its oral absorption in rats and showed significant suppression of ERK1/2 phosphorylation in an A375 melanoma xenograft model in rats by single administration. Tumor regression (T/C = -7.0%) in twice-daily repetitive studies at a dose of 50 mg/kg in rats confirmed that 6d is a promising RAF/VEGFR2 inhibitor showing potent anticancer activity.


Asunto(s)
Antineoplásicos/síntesis química , Benzamidas/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Tiazoles/síntesis química , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Administración Oral , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Benzamidas/farmacocinética , Benzamidas/farmacología , Benzoatos/síntesis química , Benzoatos/farmacocinética , Benzoatos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Línea Celular Tumoral , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Imidazoles/síntesis química , Imidazoles/farmacocinética , Imidazoles/farmacología , Ratones , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Modelos Moleculares , Estructura Molecular , Fosforilación , Piridazinas/síntesis química , Piridazinas/farmacocinética , Piridazinas/farmacología , Ratas , Relación Estructura-Actividad , Tiazoles/farmacocinética , Tiazoles/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto
15.
J Med Chem ; 54(14): 4998-5012, 2011 Jul 28.
Artículo en Inglés | MEDLINE | ID: mdl-21657270

RESUMEN

We previously discovered an orally active human gonadotropin-releasing hormone (GnRH) receptor antagonist, thieno[2,3-d]pyrimidine-2,4-dione derivative 1 (sufugolix). To reduce the cytochrome P450 (CYP) inhibitory activity and improve in vivo GnRH antagonistic activity, further optimization of this scaffold was carried out. We focused our synthetic efforts on chemical modification at the 5 and 3 positions of the thieno[2,3-d]pyrimidine-2,4-dione ring based on computational modeling, which resulted in the discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (16b) as a highly potent and orally active GnRH antagonist. Compound 16b showed potent in vitro GnRH antagonistic activity in the presence of fetal bovine serum (FBS) without CYP inhibition. Oral administration of 16b maintained the suppressive effect of the plasma luteinizing hormone levels in castrated cynomolgus monkeys at a 3 mg/kg dose for more than 24 h. Compound 16b is currently under clinical development with the code name of TAK-385.


Asunto(s)
Compuestos de Fenilurea/síntesis química , Pirimidinonas/síntesis química , Receptores LHRH/antagonistas & inhibidores , Administración Oral , Animales , Células CHO , Bovinos , Cricetinae , Cricetulus , Inhibidores del Citocromo P-450 CYP3A , Humanos , Macaca fascicularis , Masculino , Modelos Moleculares , Compuestos de Fenilurea/farmacocinética , Compuestos de Fenilurea/farmacología , Pirimidinonas/farmacocinética , Pirimidinonas/farmacología , Ensayo de Unión Radioligante , Ratas , Especificidad de la Especie , Relación Estructura-Actividad
16.
J Med Chem ; 49(13): 3809-25, 2006 Jun 29.
Artículo en Inglés | MEDLINE | ID: mdl-16789738

RESUMEN

Design, synthesis, and structure-activity relationships of thieno[2,3-b]pyridin-4-one-based non-peptide luteinizing hormone-releasing hormone (LHRH) receptor antagonists are described. Starting with the thienopyridin-4-one derivative 26d (T-98475) an optimization study was performed, which resulted in the identification of a highly potent and orally bioavailable LHRH receptor antagonist, 3-(N-benzyl-N-methylaminomethyl)-7-(2,6-difluorobenzyl)-4,7-dihydro-2-[4-(1-hydroxy-1-cyclopropanecarboxamido)phenyl]-5-isobutyryl-4-oxothieno[2,3-b]pyridine (33c). Compound 33c displayed subnanomolar in vitro activities for the human receptor and its oral administration caused effective suppression of the plasma LH levels in castrated male cynomolgus monkeys. Furthermore, SAR studies revealed that a hydroxyalkylamido moiety on the 2-phenyl ring is virtually equivalent to an alkylureido moiety, at least in this series of compounds.


Asunto(s)
Piridinas/síntesis química , Piridonas/síntesis química , Receptores LHRH/antagonistas & inhibidores , Tiofenos/síntesis química , Administración Oral , Animales , Ácido Araquidónico/metabolismo , Células CHO , Cricetinae , Cricetulus , Humanos , Macaca fascicularis , Masculino , Modelos Moleculares , Conformación Molecular , Piridinas/química , Piridinas/farmacología , Piridonas/química , Piridonas/farmacología , Ensayo de Unión Radioligante , Ratas , Especificidad de la Especie , Relación Estructura-Actividad , Tiofenos/química , Tiofenos/farmacología
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