RESUMEN
BACKGROUND: Mixed lineage leukemia 1-rearranged (MLL1-r) acute leukemia patients respond poorly to currently available treatments and there is a need to develop more effective therapies directly disrupting the MeninâMLL1 complex. Small-molecule-mediated inhibition of the proteinâprotein interaction between Menin and MLL1 fusion proteins is a potential therapeutic strategy for patients with MLL1-r or mutated-nucleophosmin 1 (NPM1c) acute leukemia. In this study, we preclinically evaluated the new compound DS-1594a and its salts. METHODS: We evaluated the preclinical efficacy of DS-1594a as well as DS-1594a·HCl (the HCl salt of DS-1594a) and DS-1594a·succinate (the succinic acid salt of DS-1594a, DS-1594b) in vitro and in vivo using acute myeloid leukemia (AML)/acute lymphoblastic leukemia (ALL) models. RESULTS: Our results showed that MLL1-r or NPM1c human leukemic cell lines were selectively and highly sensitive to DS-1594a·HCl, with 50% growth inhibition values < 30 nM. Compared with cytrabine, the standard chemotherapy drug as AML therapy, both DS-1594a·HCl and DS-1594a·succinate mediated the eradication of potential leukemia-initiating cells by enhancing differentiation and reducing serial colony-forming potential in MLL1-r AML cells in vitro. The results were confirmed by flow cytometry, RNA sequencing, RTâqPCR and chromatin immunoprecipitation sequencing analyses. DS-1594a·HCl and DS-1594a·succinate exhibited significant antitumor efficacy and survival benefit in MOLM-13 cell and patient-derived xenograft models of MLL1-r or NPM1c acute leukemia in vivo. CONCLUSION: We have generated a novel, potent, orally available small-molecule inhibitor of the Menin-MLL1 interaction, DS-1594a. Our results suggest that DS-1594a has medicinal properties distinct from those of cytarabine and that DS-1594a has the potential to be a new anticancer therapy and support oral dosing regimen for clinical studies (NCT04752163).
RESUMEN
We report the development of a new trifluoromethyltriazolobenzoxazepine series of squalene synthase inhibitors. Structure-activity studies and pharmacokinetics optimization on this series led to the identification of compound 23 (DF-461), which exhibited potent squalene synthase inhibitory activity, high hepatic selectivity, excellent rat hepatic cholesterol synthesis inhibitory activity, and plasma lipid lowering efficacy in nonrodent repeated dose studies.
RESUMEN
We recently reported that, compared to loxoprofen (LOX, an non-steroidal anti-inflammatory drug), the LOX derivative fluoro-loxoprofen (F-LOX) is less ulcerogenic but has similar anti-inflammatory activity. Our previous in vitro studies suggested that both LOX and F-LOX are pro-drugs, the active metabolites of which are their trans-alcohol forms. In this study, we compared the pharmacokinetics of F-LOX and LOX in rats. Overall, the pharmacokinetic characteristics of F-LOX, including the formation of metabolites in vivo and in vitro, were comparable to those of LOX. However, F-LOX disappeared from the plasma more rapidly than LOX, which could potentially explain its lower ulcerogenicity. However, we showed that F-LOX produced fewer gastric lesions than LOX, even when a higher plasma concentration of F-LOX was maintained. Similar to LOX, F-LOX was readily metabolized to its trans- and cis-alcohol forms, with a higher level of the trans-alcohol form being observed after oral or intravenous administration of the drug. The preferential formation of the trans-alcohol form was also observed after incubation of F-LOX with rat liver homogenates in vitro. These results suggest that, similar to LOX, F-LOX acts as a pro-drug and that there is a metabolic system that selectively produces its active metabolite.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacocinética , Fenilpropionatos/farmacocinética , Profármacos/farmacocinética , Úlcera Gástrica/inducido químicamente , Animales , Antiinflamatorios no Esteroideos/efectos adversos , Masculino , Fenilpropionatos/efectos adversos , RatasRESUMEN
In the present article, we have reported the design, synthesis, and identification of highly potent benzhydrol derivatives as squalene synthase inhibitors (compound 1). Unfortunately, the in vivo efficacies of the compounds were not enough for acquiring the clinical candidate. We continued our investigation to obtain a more in vivo efficacious template than the benzhydrol template. In our effort, we focused on a benzoxazepine ring and designed a new tricyclic scaffold by the incorporation of heterocycle into it. Prepared pyrrolobenzoxazepine derivatives showed further efficient in vitro and in vivo activities.
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Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Farnesil Difosfato Farnesil Transferasa/antagonistas & inhibidores , Administración Oral , Animales , Anticolesterolemiantes/síntesis química , Anticolesterolemiantes/química , Anticolesterolemiantes/farmacología , Compuestos de Bencidrilo/síntesis química , Compuestos de Bencidrilo/química , Compuestos de Bencidrilo/farmacología , Sitios de Unión , Callithrix , Dominio Catalítico , Células Cultivadas , Simulación por Computador , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Farnesil Difosfato Farnesil Transferasa/metabolismo , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
Described is the construction of the N-methylwelwitindolinone C core via an efficient strategy that employs a sequential rhodium carbenoid-mediated O-H insertion, Claisen rearrangement and transannular [3+2] nitrone cycloaddition.
RESUMEN
A series of 4-oxo-4H-pyrido[1,2-a]pyrimidine derivatives, substituted at the 2-position with piperidines bearing quaternary ammonium salt side chains, were synthesized and evaluated for their ability to potentiate the activity of the fluoroquinolone levofloxacin (LVFX) and the beta-lactam aztreonam (AZT) in Pseudomonas aeruginosa. Attachment of the charged entity using an N-ethylcarbamoyloxy linker led to the discovery of the highly soluble compound 22 (D13-9001), which maintained good potency in vitro and displayed excellent activity in vivo in a rat pneumonia model of P. aeruginosa.
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Antibacterianos/farmacología , Proteínas de la Membrana Bacteriana Externa/antagonistas & inhibidores , Piperidinas/farmacología , Infecciones por Pseudomonas/tratamiento farmacológico , Pseudomonas aeruginosa/efectos de los fármacos , Compuestos de Amonio Cuaternario/farmacología , Animales , Antibacterianos/administración & dosificación , Antibacterianos/química , Evaluación Preclínica de Medicamentos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Haplorrinos , Infusiones Intravenosas , Masculino , Proteínas de Transporte de Membrana , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Piperidinas/síntesis química , Piperidinas/química , Compuestos de Amonio Cuaternario/administración & dosificación , Compuestos de Amonio Cuaternario/síntesis química , Compuestos de Amonio Cuaternario/química , Ratas , Ratas Sprague-Dawley , Solubilidad , EstereoisomerismoRESUMEN
A series of 4-oxo-4H-pyrido[1,2-a]pyrimidine derivatives, derivatized at the 2-position with aromatic substituents, were synthesized by the Suzuki cross-coupling method and evaluated for their ability to potentiate the activity of the fluoroquinolone levofloxacin (LVFX) and the anti-pseudomonas beta-lactam aztreonam (AZT) in Pseudomonas aeruginosa. By incorporating hydrophilic substituents onto the aryl nucleus, we found a morpholine analogue that possessed improved solubility, retained activity in vitro, and displayed potentiation activity in vivo in a rat model of P. aeruginosa pneumonia.
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Antibacterianos/farmacología , Proteínas de la Membrana Bacteriana Externa/antagonistas & inhibidores , Pseudomonas aeruginosa/efectos de los fármacos , Pirimidinas/farmacología , Animales , Antibacterianos/síntesis química , Antibacterianos/química , Aztreonam/química , Aztreonam/farmacología , Levofloxacino , Pulmón/efectos de los fármacos , Pulmón/microbiología , Proteínas de Transporte de Membrana , Pruebas de Sensibilidad Microbiana , Ofloxacino/química , Pirimidinas/síntesis química , Pirimidinas/química , Ratas , Ratas Sprague-DawleyRESUMEN
A series of 4-oxo-4H-pyrido[1,2-a]pyrimidine derivatives, derivatized at the 2-position with carbon-linked substituents, were synthesized and evaluated for their ability to potentiate the activity of the fluoroquinolone levofloxacin (LVFX) and the anti-pseudomonas beta-lactam aztreonam (AZT) in Pseudomonas aeruginosa. Palladium-catalyzed cross-coupling methods were applied for the incorporation of aliphatic and aromatic substituents.
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Proteínas de la Membrana Bacteriana Externa/antagonistas & inhibidores , Carbono/química , Carbono/farmacología , Farmacorresistencia Bacteriana/efectos de los fármacos , Modelos Químicos , Pseudomonas aeruginosa/efectos de los fármacos , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Concentración 50 Inhibidora , Proteínas de Transporte de Membrana , Pruebas de Sensibilidad MicrobianaRESUMEN
O6-methylguanosine derivative was treated with sodium nitrite or isoamylnitrite in the presence of the carboxylic acid to give the purin-2-yl carboxylate (2), an unusual product bearing a carboxylic group at 2-position of purine moiety.
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Guanosina/análogos & derivados , Nucleósidos de Purina/síntesis química , Guanosina/química , Nucleósidos de Purina/químicaRESUMEN
Exchange of the ethylene tether in a series of pyridopyrimidine-based MexAB-OprM specific efflux pump inhibitors to an amide bond stabilized the olefin of the acrylic acid moiety, preventing facile photoisomerization to the Z-isomer. Furthermore, the activity was drastically improved in the amide tether variants, providing extremely potent acrylic acid and vinyl tetrazole analogues.
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Proteínas de la Membrana Bacteriana Externa/antagonistas & inhibidores , Farmacorresistencia Bacteriana/efectos de los fármacos , Moduladores del Transporte de Membrana , Proteínas de Transporte de Membrana/antagonistas & inhibidores , Pseudomonas aeruginosa/efectos de los fármacos , Acrilatos/farmacología , Estabilidad de Medicamentos , Isomerismo , Pruebas de Sensibilidad Microbiana , Fotoquímica , Pirimidinas/síntesis química , Pirimidinas/farmacología , Relación Estructura-ActividadRESUMEN
The addition of substituents to the pyridopyrimidine scaffold of MexAB-OprM specific efflux pump inhibitors was explored. As predicted by a pharmacophore model, the incorporation substituents at the 2-position improved potency. Piperidines were found to be optimal, and further introduction of polar groups without compromising the activity was shown to be feasible. Careful positioning of the essential acidic moiety of the pharmacophore relative to the scaffold led to the discovery of vinyl tetrazoles with still greater potency.
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Proteínas de la Membrana Bacteriana Externa/antagonistas & inhibidores , Proteínas Portadoras/antagonistas & inhibidores , Moduladores del Transporte de Membrana , Proteínas de Transporte de Membrana/antagonistas & inhibidores , Pseudomonas aeruginosa/fisiología , Pirimidinas/química , Proteínas de la Membrana Bacteriana Externa/metabolismo , Proteínas Portadoras/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Unión Proteica/fisiología , Pseudomonas aeruginosa/química , Pirimidinas/metabolismoRESUMEN
The identification of a series of compounds that specifically inhibit efflux by the MexAB-OprM pump system in Pseudomonas aeruginosa is described. Synthesis and in vitro structure-activity relationships (SARs) are outlined. Early leads lacked activity in animal models, and efforts to improve solubility and reduce serum protein binding by the introduction of polar groups are discussed.
Asunto(s)
Antibacterianos/farmacología , Proteínas de la Membrana Bacteriana Externa/metabolismo , Transporte Biológico Activo/efectos de los fármacos , Proteínas Portadoras/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/metabolismo , Animales , Antibacterianos/metabolismo , Farmacorresistencia Microbiana , Regulación Bacteriana de la Expresión Génica , Lactamas/metabolismo , Ratones , Pruebas de Sensibilidad Microbiana , Neutropenia/tratamiento farmacológico , Unión Proteica , Sepsis/tratamiento farmacológico , Albúmina Sérica/metabolismo , Relación Estructura-ActividadRESUMEN
Problems of low solubility, high serum protein binding, and lack of efficacy in vivo in first generation MexAB-OprM specific efflux pump inhibitors were addressed. Through the use of pharmacophore modelling, the key structural elements for pump inhibition were defined. Use of alternative scaffolds upon which the key elements were arrayed gave second generation leads with greatly improved physical properties and activity in the potentiation of antibacterial quinolones (levofloxacin and sitafloxacin) versus Pseudomonas aeruginosa in vivo.