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1.
Bioorg Med Chem Lett ; 29(4): 560-562, 2019 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-30616904

RESUMEN

Fluorination of metabolic hotspots in a molecule is a common medicinal chemistry strategy to improve in vivo half-life and exposure and, generally, this strategy offers significant benefits. Here, we report the application of this strategy to a series of poly-ADP ribose glycohydrolase (PARG) inhibitors, resulting in unexpected in vivo toxicity which was attributed to this single-atom modification.


Asunto(s)
Ciclopropanos/farmacología , Glicósido Hidrolasas/toxicidad , Microsomas Hepáticos/efectos de los fármacos , Administración Oral , Animales , Ciclopropanos/administración & dosificación , Ciclopropanos/química , Ciclopropanos/farmacocinética , Glicósido Hidrolasas/administración & dosificación , Glicósido Hidrolasas/química , Glicósido Hidrolasas/farmacocinética , Semivida , Humanos , Ratones , Microsomas Hepáticos/metabolismo
2.
Bioorg Med Chem Lett ; 27(14): 3190-3195, 2017 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-28545974

RESUMEN

A series of reversible inhibitors of lysine specific demethylase 1 (LSD1) with a 5-hydroxypyrazole scaffold have been developed from compound 7, which was identified from the patent literature. Surface plasmon resonance (SPR) and biochemical analysis showed it to be a reversible LSD1 inhibitor with an IC50 value of 0.23µM. Optimisation of this compound by rational design afforded compounds with Kd values of <10nM. In human THP-1 cells, these compounds were found to upregulate the expression of the surrogate cellular biomarker CD86. Compound 11p was found to have moderate oral bioavailability in mice suggesting its potential for use as an in vivo tool compound.


Asunto(s)
Histona Demetilasas/antagonistas & inhibidores , Pirazoles/química , Animales , Antígeno B7-2/metabolismo , Sitios de Unión , Dominio Catalítico , Diferenciación Celular/efectos de los fármacos , Línea Celular , Semivida , Histona Demetilasas/metabolismo , Humanos , Concentración 50 Inhibidora , Ratones , Simulación del Acoplamiento Molecular , Pirazoles/síntesis química , Pirazoles/farmacocinética , Pirazoles/farmacología , Relación Estructura-Actividad , Resonancia por Plasmón de Superficie
3.
Bioorg Med Chem Lett ; 26(11): 2724-9, 2016 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-27086121

RESUMEN

We have previously reported a series of anilinoquinazoline derivatives as potent and selective biochemical inhibitors of the RET kinase domain. However, these derivatives displayed diminished cellular potency. Herein we describe further optimisation of the series through modification of their physicochemical properties, delivering improvements in cell potency. However, whilst cellular selectivity against key targets could be maintained, combining cell potency and acceptable pharmacokinetics proved challenging.


Asunto(s)
Compuestos de Anilina/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-ret/antagonistas & inhibidores , Quinazolinas/farmacología , Compuestos de Anilina/síntesis química , Compuestos de Anilina/química , Relación Dosis-Respuesta a Droga , Humanos , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-ret/metabolismo , Quinazolinas/síntesis química , Quinazolinas/química , Relación Estructura-Actividad
5.
J Med Chem ; 61(23): 10767-10792, 2018 12 13.
Artículo en Inglés | MEDLINE | ID: mdl-30403352

RESUMEN

DNA damage repair enzymes are promising targets in the development of new therapeutic agents for a wide range of cancers and potentially other diseases. The enzyme poly(ADP-ribose) glycohydrolase (PARG) plays a pivotal role in the regulation of DNA repair mechanisms; however, the lack of potent drug-like inhibitors for use in cellular and in vivo models has limited the investigation of its potential as a novel therapeutic target. Using the crystal structure of human PARG in complex with the weakly active and cytotoxic anthraquinone 8a, novel quinazolinedione sulfonamides PARG inhibitors have been identified by means of structure-based virtual screening and library design. 1-Oxetan-3-ylmethyl derivatives 33d and 35d were selected for preliminary investigations in vivo. X-ray crystal structures help rationalize the observed structure-activity relationships of these novel inhibitors.


Asunto(s)
Reparación del ADN , Diseño de Fármacos , Inhibidores de Glicósido Hidrolasas/química , Inhibidores de Glicósido Hidrolasas/farmacología , Glicósido Hidrolasas/antagonistas & inhibidores , Quinazolinonas/química , Quinazolinonas/farmacología , Administración Oral , Animales , Disponibilidad Biológica , Dominio Catalítico , Inhibidores de Glicósido Hidrolasas/administración & dosificación , Inhibidores de Glicósido Hidrolasas/farmacocinética , Glicósido Hidrolasas/química , Glicósido Hidrolasas/metabolismo , Células HeLa , Humanos , Masculino , Ratones , Modelos Moleculares , Quinazolinonas/administración & dosificación , Quinazolinonas/farmacocinética , Relación Estructura-Actividad
6.
Eur J Med Chem ; 112: 20-32, 2016 Apr 13.
Artículo en Inglés | MEDLINE | ID: mdl-26874741

RESUMEN

Deregulation of the receptor tyrosine kinase RET has been implicated in medullary thyroid cancer, a small percentage of lung adenocarcinomas, endocrine-resistant breast cancer and pancreatic cancer. There are several clinically approved multi-kinase inhibitors that target RET as a secondary pharmacology but additional activities, most notably inhibition of KDR, lead to dose-limiting toxicities. There is, therefore, a clinical need for more specific RET kinase inhibitors. Herein we report our efforts towards identifying a potent and selective RET inhibitor using vandetanib 1 as the starting point for structure-based drug design. Phenolic anilinoquinazolines exemplified by 6 showed improved affinities towards RET but, unsurprisingly, suffered from high metabolic clearance. Efforts to mitigate the metabolic liability of the phenol led to the discovery that a flanking substituent not only improved the hepatocyte stability, but could also impart a significant gain in selectivity. This culminated in the identification of 36; a potent RET inhibitor with much improved selectivity against KDR.


Asunto(s)
Piperidinas/química , Piperidinas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-ret/antagonistas & inhibidores , Quinazolinas/química , Quinazolinas/farmacología , Animales , Línea Celular , Diseño de Fármacos , Humanos , Ratones , Simulación del Acoplamiento Molecular , Piperidinas/farmacocinética , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Proto-Oncogénicas c-ret/metabolismo , Quinazolinas/farmacocinética
7.
J Med Chem ; 56(16): 6352-70, 2013 Aug 22.
Artículo en Inglés | MEDLINE | ID: mdl-23859074

RESUMEN

The recently discovered enzyme tyrosyl-DNA phosphodiesterase 2 (TDP2) has been implicated in the topoisomerase-mediated repair of DNA damage. In the clinical setting, it has been hypothesized that TDP2 may mediate drug resistance to topoisomerase II (topo II) inhibition by etoposide. Therefore, selective pharmacological inhibition of TDP2 is proposed as a novel approach to overcome intrinsic or acquired resistance to topo II-targeted drug therapy. Following a high-throughput screening (HTS) campaign, toxoflavins and deazaflavins were identified as the first reported sub-micromolar and selective inhibitors of this enzyme. Toxoflavin derivatives appeared to exhibit a clear structure-activity relationship (SAR) for TDP2 enzymatic inhibition. However, we observed a key redox liability of this series, and this, alongside early in vitro drug metabolism and pharmacokinetics (DMPK) issues, precluded further exploration. The deazaflavins were developed from a singleton HTS hit. This series showed distinct SAR and did not display redox activity; however low cell permeability proved to be a challenge.


Asunto(s)
Hidrolasas Diéster Fosfóricas/efectos de los fármacos , Pirimidinonas/farmacología , Inhibidores de Topoisomerasa II/farmacología , Triazinas/farmacología , Relación Estructura-Actividad , Inhibidores de Topoisomerasa II/química
8.
J Med Chem ; 55(9): 4431-45, 2012 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-22506561

RESUMEN

Novel derivatives of the steroid DHEA 1, a known uncompetitive inhibitor of G6PD, were designed, synthesized, and tested for their ability to inhibit this dehydrogenase enzyme. Several compounds with approximately 10-fold improved potency in an enzyme assay were identified, and this improved activity translated to efficacy in a cellular assay. The SAR for steroid inhibition of G6PD has been substantially developed; the 3ß-alcohol can be replaced with 3ß-H-bond donors such as sulfamide, sulfonamide, urea, and carbamate. Improved potency was achieved by replacing the androstane nucleus with a pregnane nucleus, provided a ketone at C-20 is present. For pregnan-20-ones incorporation of a 21-hydroxyl group is often beneficial. The novel compounds generally have good physicochemical properties and satisfactory in vitro DMPK parameters. These derivatives may be useful for examining the role of G6PD inhibition in cells and will assist the future design of more potent steroid inhibitors with potential therapeutic utility.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Glucosafosfato Deshidrogenasa/antagonistas & inhibidores , Pregnanos/química , Pregnanos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Supervivencia Celular/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Glucosafosfato Deshidrogenasa/metabolismo , Células HEK293 , Humanos , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Pregnanos/síntesis química , Pregnanos/farmacocinética , Relación Estructura-Actividad
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