ES2550052T3 - Bloqueadores de los canales sódicos triazoicos cíclicos - Google Patents

Bloqueadores de los canales sódicos triazoicos cíclicos Download PDF

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ES2550052T3
ES2550052T3 ES10732408.9T ES10732408T ES2550052T3 ES 2550052 T3 ES2550052 T3 ES 2550052T3 ES 10732408 T ES10732408 T ES 10732408T ES 2550052 T3 ES2550052 T3 ES 2550052T3
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sodium channel
triazoic
cyclic
channel blockers
compounds
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Michael Leach
Karl Franzmann
Dieter Riddall
Laurence Harbige
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University of Greenwich
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    • C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
    • C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
    • C07D253/06—1,2,4-Triazines
    • C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
    • C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

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Abstract

Un compuesto seleccionado entre:**Fórmula**

Description

imagen1
imagen2
imagen3
imagen4
E10732408
13-10-2015
imagen5
Ensayo biológico
Se testaron ciertos componentes para diversas actividades de la siguiente manera:
Estrategia de exploración
5 La estrategia de exploración se diseña para seleccionar compuestos con actividad bloqueadora de los canales de sodio apropiada y bajo riesgo de efectos secundarios. Con este fin todos los compuestos se procesan a través de la prueba de los canales de sodio primarios (captación de [14C]guanidina provocada por veratrina en sinaptosomas de cerebro anterior de rata) y los valores de CI50 se calcularon a partir de las curvas de concentración-efecto generadas. Para complementar estos datos, se miden también las CI50 de compuestos seleccionados para inhibir la
10 unión de [3H]BTX-B.
Los estudios previos han demostrado que las triazinas sustituidas son inhibidores potenciales de la actividad de la dihidrofolato reductasa (DHFR) (McCullough y Bertino 1971, Cashmore y col, 1975, Booth y col, 1987) y Sapse y col, 1994). Los inhibidores de la DHFR (tales como Metotrexato) se han utilizado para el tratamiento de varios tipos de
6
imagen6
imagen7
5
10
15
20
25
30
35
E10732408
13-10-2015
2.
Reiner PB, Laycock AG, Doll CJ. A pharmacological model of ischemia in the hippocampal slice. Neurosci Lett 1990; 119:175-8
3.
Boening JA, Kass IS, Cottrell JE, Chambers G. The effect of blocking sodium influx on anoxic damage in the rat hippocampal slice. Neuroscience. 1989. vol 33 (2), 263-268.
Medición de ATP y proteína
Los cortes individuales se interrumpieron por ultrasonidos y los homogeneizados resultantes se centrifugaron a 10000 x g durante 5 min a 4 ºC. El sobrenadante se decantó en un tubo nuevo y el sobrenadante restante se eliminó mediante aspiración al vacío. El pellet se volvió a suspender en 0,5 ml de KOH 0,1 M por ultrasonidos y las suspensiones resultantes se calentaron con agitación suave a 37 ºC durante 30 minutos.
Las concentraciones de ATP se midieron en 6 µl de sobrenadante mezclando con reactivo de luciferasa (ATPLite de Perkin Elmer) y midiendo posteriormente la luminiscencia en un contador de placa de 96 pocillos.
La concentración de proteína se midió utilizando el ensayo de proteína BCA™ (Pierce) con albúmina de suero bovina como patrón de referencia.
Las concentraciones de ATP se expresaron como nmoles/mg de proteína y los índices neuroprotectores (% de protección) se calcularon por comparación directa con el efecto de TTX de 1 µM.
hERG:
Los compuestos se enviaron a MDS Pharma para medir su inhibición en concentración de 10 µM de la unión de [3H] astemizol a las células HEK-293 que expresan hERG recombinante humano. Haciendo la suposición de que las pendientes de unión son 1,0, se podrían calcular los valores CI50 (véase anteriormente) para los compuestos que presentan una inhibición de unión entre 5% y 95%.
Canales de calcio tipo L
Los compuestos se enviaron a MDS Pharma para medir su inhibición en concentración de 10 µM de la unión de [3H] nitrendipino a las membranas de corteza cerebral de rata. Haciendo la suposición de que las pendientes de unión son 1,0, se podrían calcular los valores de CI50 (véase anteriormente) para los compuestos que presentan una inhibición de unión entre 5% y 95%.
Estabilidad en microsomas de rata
Los compuestos se enviaron a BioFocus para medir su estabilidad en concentración de 1 µM después de la incubación con microsomas de hígado de rata durante 40 minutos a 37 ºC.
Los datos de la exploración se obtuvieron con respecto a los compuestos representativos de los puntos de la invención a la idoneidad de los compuestos de la reivindicación 1 para el tratamiento de trastornos en mamíferos que son susceptibles a los bloqueadores de los canales del sodio y antifolatos, y en particular trastornos tales como epilepsia, esclerosis múltiple, glaucoma y uveítis, traumatismos cerebrales e isquemias cerebrales, apoplejía, lesión en la cabeza, lesión en la médula espinal, traumatismo quirúrgico, trastornos neurodegenerativos, trastorno de la neurona motora, enfermedad de Alzheimer, enfermedad de Parkinson, dolor crónico inflamatorio, dolor neuropático, migraña, trastorno bipolar, trastornos del estado de ánimo, ansiedad y cognitivo, esquizofrenia y cefaleas trigémino autonómicas.
Los datos de los procedimientos se exponen en la siguiente tabla:
Estructura del compuesto Nº
Nach ([3H]BTX-B) (µM CI50 extrapolada) DHFR (% de inhibición en 125 µM)
23
0
9
E10732408
13-10-2015
(continuación)
Estructura del compuesto Nº
Nach ([3H]BTX-B) (µM DHFR (% de
CI50 extrapolada)
inhibición en 125 µM)
1
ND
imagen8
5 100
3
22
imagen9
8 63
imagen10
4 14
imagen11
< 0,5 70
10
E10732408
13-10-2015
(continuación)
Estructura del compuesto Nº
Nach ([3H]BTX-B) (µM CI50 extrapolada) DHFR (% de inhibición en 125 µM)
imagen12
>190 < 0,5 > 190 y 31,7 < 0,5 y 1,5 115 9 ND 73 8 90 0 0
(CEN-001) Resultado de lamotrigina utilizando la prep de enzima en 125 micromolar dio una inhibición del 26%
11

Claims (1)

  1. imagen1
    imagen2
ES10732408.9T 2009-07-08 2010-07-08 Bloqueadores de los canales sódicos triazoicos cíclicos Active ES2550052T3 (es)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB0911993A GB2471713A (en) 2009-07-08 2009-07-08 1,2,4-triazine derivatives and their use as sodium channel blockers
GB0911993 2009-07-08
PCT/GB2010/051127 WO2011004196A1 (en) 2009-07-08 2010-07-08 Cyclic triazo sodium channel blockers

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ES2550052T3 true ES2550052T3 (es) 2015-11-04

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ES10732408.9T Active ES2550052T3 (es) 2009-07-08 2010-07-08 Bloqueadores de los canales sódicos triazoicos cíclicos

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US (1) US8748600B2 (es)
EP (1) EP2451807B1 (es)
JP (1) JP5847079B2 (es)
KR (1) KR20120048593A (es)
CN (1) CN102482266B (es)
AU (1) AU2010269982B2 (es)
CA (1) CA2767298A1 (es)
ES (1) ES2550052T3 (es)
GB (1) GB2471713A (es)
IL (1) IL217330B (es)
IN (1) IN2012DN00871A (es)
WO (1) WO2011004196A1 (es)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0800741D0 (en) 2008-01-16 2008-02-20 Univ Greenwich Cyclic triazo and diazo sodium channel blockers
GB2471729A (en) * 2009-07-08 2011-01-12 Univ Greenwich 1,2,4-triazine derivatives and their use as sodium channel blockers
ES2858750T3 (es) * 2015-06-12 2021-09-30 Univ Greenwich Derivados de triazina como inhibidores del interferón gamma
AU2017233841B9 (en) 2016-03-14 2021-09-09 Afferent Pharmaceuticals Inc. Pyrimidines and variants thereof, and uses therefor
US10662162B2 (en) 2016-03-25 2020-05-26 Afferent Pharmaceuticals, Inc. Pyrimidines and variants thereof, and uses therefor
JP6679093B1 (ja) * 2018-11-26 2020-04-15 大学共同利用機関法人自然科学研究機構 ナトリウムチャンネルおよび酸感受性イオンチャンネルの機能阻害を標的とした阻害剤及び治療剤のスクリーニング方法とその用途

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3637688A (en) * 1970-01-09 1972-01-25 American Home Prod 6-(fluoro and trifluoromethyl phenyl)-3 5-diamino - 1 2 4 - triazines and substituted - 6 - phenylalkyl-3,5-diamino-1 2 4-triazines
AU530999B2 (en) 1979-06-01 1983-08-04 Wellcome Foundation Limited, The Substituted amino triazines and their use in treatment of cns disorders
GB8328757D0 (en) * 1983-10-27 1983-11-30 Wellcome Found Chemical compounds
DE10134980C2 (de) * 2001-07-17 2003-05-28 Helm Ag Verfahren zur Herstellung von Lamotrigin
GB0613836D0 (en) * 2006-07-13 2006-08-23 Univ Greenwich New medical use of triazine derivatives
GB0800741D0 (en) * 2008-01-16 2008-02-20 Univ Greenwich Cyclic triazo and diazo sodium channel blockers

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CN102482266A (zh) 2012-05-30
AU2010269982A1 (en) 2012-02-16
JP5847079B2 (ja) 2016-01-20
AU2010269982B2 (en) 2015-05-14
CN102482266B (zh) 2015-07-08
IN2012DN00871A (es) 2015-07-10
IL217330A0 (en) 2012-02-29
EP2451807B1 (en) 2015-09-02
IL217330B (en) 2018-12-31
EP2451807A1 (en) 2012-05-16
GB2471713A (en) 2011-01-12
JP2012532858A (ja) 2012-12-20
US20120135993A1 (en) 2012-05-31
GB0911993D0 (en) 2009-08-19
KR20120048593A (ko) 2012-05-15
CA2767298A1 (en) 2011-01-13
US8748600B2 (en) 2014-06-10
WO2011004196A1 (en) 2011-01-13

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