ES2553610T3 - Inhibidores de la caseína cinasa 1 delta (CK1delta) - Google Patents

Inhibidores de la caseína cinasa 1 delta (CK1delta) Download PDF

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Publication number
ES2553610T3
ES2553610T3 ES11804754.7T ES11804754T ES2553610T3 ES 2553610 T3 ES2553610 T3 ES 2553610T3 ES 11804754 T ES11804754 T ES 11804754T ES 2553610 T3 ES2553610 T3 ES 2553610T3
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alkyl
aryl
tau
heteroaryl
groups
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Joseph M. Sheridan
Jonathan R. Heal
William D.O. Hamilton
Ian Pike
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Electrophoretics Ltd
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Electrophoretics Ltd
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Priority claimed from GBGB1021161.3A external-priority patent/GB201021161D0/en
Priority claimed from GBGB1109162.6A external-priority patent/GB201109162D0/en
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
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    • C—CHEMISTRY; METALLURGY
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    • C—CHEMISTRY; METALLURGY
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    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D495/14—Ortho-condensed systems

Abstract

Una composición farmacéutica que comprende un compuesto de fórmula (IB) o una sal farmacéuticamente aceptable o un solvato del mismo: en donde "Het B" representa indolilo o indolizinilo; Z representa CO; R1b representa arilo, cicloalquilo C3-8, heterociclilo monocíclico o bicíclico o un sistema de anillos de heteroarilo monocíclico o bicíclico, en donde R1b puede estar sustituido por uno o varios (p. ej., 1, 2 o 3) grupos R4b; R4b representa grupos halógeno, alquilo C1-6, alquenilo C1-6, alquinilo C1-6, cicloalquilo C3-8, haloalquilo C1-6, hidroxilo, alcoxi C1-6, -O-alquenilo C1-6, haloalcoxi C1-6, -COOH, -CO-alquilo C1-6, -COO-alquilo C1-6, -CONH2, -CH2-CONH2, -NH-alquilo C1-6, -NH-alquenilo C2-6, -NH-CO-alquilo C1-6, -CO-NH-alquilo C1-6, -O-CH2-CO-NH-alquilo C1-6, -CH2- CH2-CO-NH-alquilo C1-6, -S-alquilo C1-6, -SO-alquilo C1-6, -SO2-alquilo C1-6, -SO2-NH2, -SO2-NH-alquilo C1-6, -S-CH2- CO-alquenilo C2-6, -SO2-OH, amino, ciano, NO2, >=O, -CO-NH-(CH2)2)-OMe, -NH-cicloalquilo C3-8, -CH2-CO-NH cicloalquilo C3-8, -CO-heterociclilo, -CO-heteroarilo, -COO-(CH2)2-heterociclilo, -CH2-arilo, -OCH2-arilo, -OCH2- heteroarilo, -CH2-O-CO-arilo, -O-arilo, -NH-CO-arilo, -NH-CO-heteroarilo, -NH-CO-CH2-arilo, -NH-arilo, arilo o heteroarilo, en donde dichos grupos arilo, heterociclilo o heteroarilo de R4b pueden estar opcionalmente sustituidos con uno o varios grupos halógeno, alquilo C1-6, alcoxi C1-6, >=S o hidroxilo y en donde dichos grupos alquilo C1-6 o alquenilo C2-6 de R4b pueden estar opcionalmente sustituidos con uno o varios grupos hidroxilo, amino, ciano, alcoxi C1-6, CONH2 o -COO-alquilo C1-6; m representa 2; y R2b representa amino o -CONH2.

Description

imagen1
DESCRIPCIÓN
Inhibidores de la caseína cinasa 1delta (CK1δ)
La invención se refiere a composiciones farmacéuticas que comprenden inhibidores de la caseína cinasa 1 delta (CK1δ) y al uso de dichos inhibidores en el tratamiento de trastornos neurodegenerativos tales como la enfermedad 5 de Alzheimer.
La enfermedad de Alzheimer (EA; también conocida como demencia senil de tipo Alzheimer (DSTA), demencia degenerativa primaria de tipo Alzheimer (DTA) o Alzheimer) es la forma más común de demencia. Muy frecuentemente, la enfermedad de Alzheimer se diagnostica en personas mayores de 65 años de edad, aunque el Alzheimer de inicio temprano, menos frecuente, puede producirse mucho antes. En el año 2006, había 26,6 millones
10 de enfermos en todo el mundo. Se prevé que el Alzheimer afectará a 1 de cada 85 personas globalmente en el año 2050.
La enfermedad de Alzheimer es una enfermedad neurodegenerativa caracterizada por la presencia de placas seniles y ovillos neurofibrilares en el cerebro. El grado de demencia al morir se correlaciona mejor con el número de ovillos neurofibrilares que con el recuento de placas seniles. La presencia de ovillos neurofibrilares en las neuronas 15 produce como resultado la muerte de esas neuronas, lo que implica que una prevención de la formación de ovillos es un objetivo terapéutico importante. La principal proteína que forma el ovillo neurofibrilar es la proteína asociada a microtúbulos, tau, la cual se ensambla en filamentos que tienen la apariencia de girar uno sobre otro en parejas y se conocen como filamentos helicoidales emparejados (FHA). Los FHA están presentes en diferentes lugares en neuronas degeneradas en el cerebro de Alzheimer y cuando se agregan muchos en el cuerpo celular neuronal,
20 producen el ovillo neurofibrilar (Lee et al, 2001).
Los depósitos intraneuronales de tau en forma de ovillos neurofibrilares típicos de la EA u otros agregados de tau morfológicamente distintos, en una variedad de otras enfermedades neurodegenerativas, son la base para agrupar estas afecciones como tauopatías. Por lo tanto, además de la EA, los principales ejemplos de tauopatías son la demencia frontotemporal con parkinsonismo, ligada al cromosoma 17 (FTDP-17), la parálisis supranuclear
25 progresiva (PSP), la enfermedad de Pick, la degeneración corticobasal y la atrofia multisistémica (MSA). Los depósitos intracelulares de tau (usualmente neuronales pero también pueden ser gliales) son todos filamentosos y en su mayoría en un estado hiperfosforilado, en comparación con el nivel de fosforilación de tau de un cerebro humano de control. En el caso de la EA, esta tau hiperfosforilada se conoce frecuentemente como FHA-tau, ya que se obtiene a partir de los FHA.
30 Tau es una fosfoproteína en la que la función de fosforilación todavía no se ha establecido de forma inequívoca. Sin embargo, un aumento de la fosforilación de tau en múltiples residuos de serina y treonina reduce la capacidad de tau para favorecer el ensamblaje de los microtúbulos y estabilizar los microtúbulos ensamblados, efectos que se han demostrado tanto in vitro como en células. Muchos estudios han mostrado que FHA-tau de cerebro con EA se fosforila más fuertemente en serina y treonina que tau de un cerebro control. Esto se ha demostrado en parte
35 mediante la secuenciación de proteínas y en parte mediante la demostración de que ciertos anticuerpos monoclonales solo marcan ya sea FHA-tau o tau no fosforilada y no FHA-tau; en los epítopos de muchos de estos anticuerpos se han cartografiado en particular residuos fosforilados presentes en FHA-tau y ausentes de la tau de un cerebro control. La tau patológica de la mayoría de otros casos de tauopatías, parece estar hiperfosforilada de manera similar a FHA-tau.
40 Estos resultados implican fuertemente que anomalías similares en la regulación de la fosforilación de tau se comparten en todas los tauopatías, incluyendo EA.
Se ha sugerido que un número de proteínas cinasas dirigidas a prolina y no dirigidas a prolina tienen un papel en la generación de FHA-tau en el cerebro del Alzheimer, incluyendo la caseína cinasa 1. La caseína cinasa 1 de mamífero está presente en forma de múltiples isoformas CK1α, CK1β, CK1y1, CK1y2, CK1y3, CK1δ y CK1ε. El 45 papel de CK1δ como una cinasa de tau potencial es de particular interés ya que se ha informado de que la proteína CK1δ se incrementa más de 30 veces en el hipocampo de un cerebro con Alzheimer, en comparación con controles equivalentes (Ghoshal, N. et al (1999) Am. J. Pathol 155, 1163-1172) mientras que su contenido en ARNm se incrementa 24 veces (Yasojima, K. et al (2000) Brain Res 865, 116-120) y se ha observado que CK1 también está fuertemente asociada con FHA (Kuret, J.et al (1997) J. Neurochem 69, 2506-2515). También se ha informado de 50 que CK1δ fosforila tau en dos epítopos detectados usando anticuerpos monoclonales fosfoespecíficos para tau, y la expresión exógena de CK1δ en células no neuronales reduce la unión de tau a los microtúbulos (Li, G. et al (2004) J. Biol. Chem. 279, 15938-15945). Es de destacar en el contexto de la enfermedad de Alzheimer, un informe de que la actividad de CK1 está estimulada por péptido beta-amiloide (Αβ), un componente de las placas neuríticas seniles que, junto con los ovillos, caracterizan un cerebro de Alzheimer (Chauhan, A. et al (1993) Brain Res. 629, 47-52). 55 Una evidencia adicional de una posible participación de CK1 en la enfermedad de Alzheimer, proviene de la influencia mencionada de CK1 en la regulación de la producción de Αβ en las neuronas (Flajolet, M. et al (2007) PNAS USA 104, 4159-4164). Un trabajo adicional ha confirmado que al menos 6 sitios de fosforilación identificados recientemente en FHA-tau (todos en residuos de serina o treonina) pueden ser generados por CK1δ. El hallazgo de una variedad de sitios de fosforilación en FHA-tau para los que CK1 es una cinasa candidata importante, incluyendo
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Las referencias en esta memoria a "heteroarilo" significan un anillo aromático que contiene de 1 a 4 heteroátomos como átomos miembros en el anillo. Los grupos heteroarilo que contienen más de un heteroátomo, pueden contener heteroátomos diferentes. Los grupos heteroarilo pueden estar opcionalmente sustituidos con uno o varios sustituyentes como se define en esta memoria. Los grupos heteroarilo son sistemas de anillos monocíclicos o son 5 sistemas de anillos bicíclicos o policíclicos fusionados. Los anillos de heteroarilo monocíclicos tienen 5 o 6 átomos miembros. Los anillos de heteroarilo bicíclicos tienen de 7 a 11 átomos miembros. Los anillos de heteroarilo bicíclicos incluyen aquellos anillos en los que un fenilo y un anillo de heterociclilo monocíclico están unidos formando un sistema de anillos bicíclicos condensados, y aquellos anillos en los que un anillo heteroarilo monocíclico y un anillo cicloalquilo, cicloalquenilo, heterociclilo o heteroarilo monocíclico están unidos formando un sistema de anillos
10 bicíclicos fusionados. Ejemplos no limitantes de heteroarilo incluyen pirrolilo, pirazolilo, imidazolilo, oxazolilo, isoxazolilo, tiazolilo, isotiazolilo, furanilo, furazanilo, tienilo, triazolilo, piridinilo, pirimidinilo, piridazinilo, pirazinilo, triazinilo, tetrazinilo, indolilo, isoindolilo, indolizinilo, indazolilo, purinilo, quinolinilo, isoquinolinilo, quinoxalinilo, quinazolinilo, pteridinilo, cinolinilo, bencimidazolilo, benzopiranilo, benzoxazolilo, benzofuranilo, isobenzofuranilo, benzotiazolilo, benzotienilo, furopiridinilo y naftiridinilo.
15 Las referencias en esta memoria a "sistema de anillos heterocíclicos" significan un sistema de anillos heterociclilos o un sistema de anillos heteroarilos como se han definido anteriormente.
Compuestos representativos de fórmula (IB) incluyen los compuestos tal y como se describen a continuación:
Número de Compuesto
Estructura
847
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987
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990
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999
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Compuestos comparativos de fórmula (IB) incluyen los compuestos tal y como se describen a continuación:
Número de compuesto
Estructura
2
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3
imagen11
26
imagen12
27
imagen13
28
imagen14
30
imagen15
31
imagen16
32
imagen17
Número de compuesto
Estructura
33
imagen18
35
imagen19
47
imagen20
48
imagen21
51
imagen22
54
imagen23
57
imagen24
Número de compuesto
Estructura
58
imagen25
59
imagen26
60
imagen27
63
imagen28
64
imagen29
78
imagen30
Número de compuesto
Estructura
84
imagen31
113
imagen32
123
imagen33
127
imagen34
128
imagen35
129
imagen36
Número de compuesto
Estructura
145
imagen37
155
imagen38
156
imagen39
157
imagen40
171
imagen41
172
imagen42
Número de compuesto
Estructura
173
imagen43
204
imagen44
206
imagen45
207
imagen46
210
imagen47
225
imagen48
Número de compuesto
Estructura
227
imagen49
233
imagen50
235
imagen51
236
imagen52
241
imagen53
242
imagen54
Número de compuesto
Estructura
244
imagen55
249
imagen56
269
imagen57
285
imagen58
288
imagen59
303
imagen60
Número de compuesto
Estructura
307
imagen61
308
imagen62
309
imagen63
310
imagen64
311
imagen65
312
imagen66
314
imagen67
Número de compuesto
Estructura
315
imagen68
316
imagen69
320
imagen70
324
imagen71
325
imagen72
333
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V2 está fosforilado únicamente por CK1δ y existe una posibilidad de que la inhibición inducida por el compuesto de la fosforilación medida por este método, se puede lograr a través de una inhibición promiscua de otras cinasas, tales como GSK3b y/o CDK5. Para hacer frente a esta limitación, Proteome Sciences ha desarrollado un ensayo V3 que mide la tau total y dos sitios que se fosforilan exclusivamente con CK1δ, además de otros cuatro que se han observado que se fosforilan in vitro con al menos otra cinasa Tau además de CK1δ. La Tabla 1 enumera los diferentes sitios ocupados y las cinasas Tau candidatas descritas en Hanger et al. (2007).
Tabla 1: Sitios de fosforilación de Tau ocupados mediante ensayos de fosforilación de Tau SRM V2 y V3
Número de sitio
Cinasas candidatas
Ensayo V2
Ser181
GSK3b
Ser199
CK2, GSK3b, PKA
Thr231
GSK3b, PKA
Ser262
CK1δ, GSK3b, PKA
Ser396
CK1δ, CK2, GSK3b
Ensayo V3
Ser46
CK1δ, GSK3b
Thr50
CK1δ, GSK3b
Ser113*
CK1δ
Ser396
CK1δ, CK2, GSK3b
Ser404
CK1δ, CK2, GSK3b
Ser433*
CK1δ
Numeración basada en tau 2N4R humana.
* -sitio único CK1d
10 Línea celular SH-SY5Y-TMHT
La línea celular SH-SY5Y-TMHT (JSW Life Sciences, Graz, Austria) representa un modelo in vitro de tauopatía. La línea celular se crea transfectando de forma estable la línea celular SH-SY5Y obtenida a partir de neuroblastoma humano, con un vector que contiene toda la isoforma de Tau 2N4R humana de longitud completa que es portadora de dos mutaciones comunes asociadas con la enfermedad (V337M/R406W). En estudios recientes (Flunkert et al. 15 presentado en 2011, Loeffler et al. presentado en 2011) tanto la línea celular SH-SY5Y-TMHT como la línea de ratón transgénico que es portadora del mismo transgén humano, mostraron un alto nivel de expresión de Tau humana que se había hiperfosforilado en múltiples epítopos, lo que se había demostrado previamente en varias tauopatías humanas incluyendo la enfermedad de Alzheimer. Además, en las células SH-SY5Y-TMHT expuestas a diferentes inhibidores de cinasas, incluyendo el inhibidor de JNK SP600125 y el inhibidor de CK1 IC261, los niveles de
20 fosforilación de Tau en los sitios patogénicos clave se redujeron en patrones consistentes con la especificidad del sitio conocida de la cinasa específica. Por tanto, la línea celular SH-SY5Y-TMHT es muy adecuada para el escrutinio de nuevos inhibidores de la cinasa Tau.
5
10
15
20
25
30
Escrutinio del compuesto en células SH-SY5Y-TMHT
Las células SH-SY5Y-TMHT se cultivan en medio de cultivo (medio DMEM, 10% de FCS, 1% de NEAA, 1% de Lglutamina, 100 µg/ml de gentamicina, 300 µg/ml de geneticina G-418) durante 2 días hasta tener 80-90% de confluencia. A continuación, las células se diferencian en medio de cultivo complementado con ácido retinoico (AR) 10 μΜ durante 7 días, cambiando el medio cada 2 a 3 días. Las células diferenciadas se siembran en placas de 6 pocillos y placas de 96 pocillos con una densidad celular de 1,25 x 106 y 8 x 105 células por pocillo, respectivamente. El día 8 después de la diferenciación, se añadieron los compuestos del ensayo, los compuestos de referencia y el vehículo de control al medio de cultivo. Después de 6 h de exposición del compuesto, una placa de células se sometió a un ensayo MTT para evaluar el efecto de los elementos del ensayo y de referencia sobre la viabilidad celular. Los pocillos restantes se lavan una vez con PBS sin radiactividad y se recogen en 300 μΙ de tampón RIPA [Tris 50 mM pH 7,4, 1% de Nonident P40, 0,25% de Na-desoxi-colato, NaCl 150 mM, EDTA 1 mM, NaF 1 μΜ, Naorto-vanadato 1 μΜ, glicerofosfato 80 mM, complementado con proteasa recién añadida (Calbiochem) y mezcla de inhibidor de fosfatasa (Sigma)]. La suspensión celular se transfiere a un tubo de 1,5 ml y, además, se lisa mediante ultrasonidos sobre hielo. Se toma una parte alícuota de 20 μΙ para determinar la concentración de proteína (ensayo BCA). Posteriormente, los lisados se congelan rápidamente y se almacenan a -80°C hasta su envío.
Dos experimentos independientes en tres (cuatro) replicados técnicos, se llevan a cabo como se muestra en la Tabla 2.
Tabla 2
imagen212
Pruebas de viabilidad de la célula
Para determinar la actividad del compuesto, es necesario controlar la toxicidad celular potencial de todas las moléculas. La viabilidad de los cultivos se determina mediante el ensayo MTT. Este ensayo permite la medición de la actividad deshidrogenasa mitocondrial que reduce el MTT amarillo a cristales de formazán de color azul oscuro. Dado que esta reacción está catalizada en las células vivas, este ensayo se utiliza solamente para la determinación de la viabilidad celular. La solución de MTT se añade a cada pocillo con una concentración final de 0,5 mg/ml. Después de 2 horas, el medio que contiene MTT se aspira. Las células se lisan en 3% de SDS y los cristales de formazán se disuelven en isopropanol/HCl. La densidad óptica se mide con un lector de placas a una longitud de onda de 570 nm. La tasa de supervivencia celular se expresa como densidad óptica (DO). Los valores se calculan como el porcentaje de los valores de control.
Determinación cuantitativa del contenido total en proteína
Antes de la evaluación del estado de fosforilación específica de Tau, la concentración de proteína total en cada lisado celular se determina usando un ensayo BCA estándar (Pierce Biotechnology, Rockford, EE.UU.) Brevemente, se utilizaron 20 μΙ de lisado celular en el ensayo de acuerdo con las instrucciones del fabricante.
imagen213
concentración de proteína de las muestras estaba en el intervalo esperado, de acuerdo con la cantidad de células sembradas por placa de 12 pocillos, que oscilaba entre 150-350 µg/ml.
Determinación del efecto del tratamiento del compuesto sobre los sitios de fosforilación específicos
Ensayo de espectrometría de masas
5 El ensayo de los lisados de células SH-SY5Y-TMHT se realizó usando el ensayo de V2 y V3 de PhosphoTau SRM. Cuando el nivel relativo de fosforilación en cada sitio se comparaba con la proporción en los controles tratados con vehículo, había una clara reducción del nivel de fosfopéptidos en las células tratadas con el Compuesto 324 (datos mostrados para 10 μΜ) y el Compuesto 987 (datos mostrados para 10 μΜ). Un ejemplo que muestra una reducción de la fosforilación en la serina 396 se muestra en la Figura 4. Esta Figura muestra la determinación de la
10 espectrometría de masas de compuestos selectivos para CK1d sobre la fosforilación de la serina 396 en las células SH-SY5Y-TMHT. El panel A muestra las células tratadas con vehículo de control (VC) o el Compuesto 324 (Τ.Ι.1_10μΜ) y el Panel B muestra las células tratadas con vehículo de control (VC) o el Compuesto 987 (T.I.2_10μΜ).
En las células expuestas al vehículo de control, aproximadamente el 83% de Tau se fosforila en S396. El tratamiento
15 con el Compuesto 324 10 μΜ reduce este valor al 38%, mientras que el Compuesto 987 10 μΜ reduce los niveles de pS396 al 24%. Estos resultados confirman la inhibición de pS396 a través de reactivos selectivos de CK1d.
Ensayo de transferencia Western
Los niveles de Tau total y Tau fosforilada en la treonina 231 en lisados de células SH-SY5Y-TMHT tratados con el vehículo de control, el Compuesto 394 (10 μΜ), el Compuesto 987 (10 μΜ) y PF670462 (5 μΜ), se cuantificaron 20 mediante una transferencia Western. La Figura 5 muestra la medición de la transferencia Western de pT231 (panel A) y los niveles de Tau total (panel B) en las células SH-SY5Y-TMHT tratadas con inhibidores selectivos de CK1d. Como se muestra en la Figura 5, los tres compuestos reducían el nivel detectable de pT231 en la proteína Tau, mientras que este epítopo estaba muy presente en las células tratadas con vehículo. No había una diferencia significativa en los niveles detectables de Tau total entre las preparaciones que eran distintas del lisado tratado con
25 PF670462, el cual parecía contener marginalmente menos Tau total que las otras. Estos resultados confirman la inhibición de pT231 a través de reactivos selectivos de CK1d.

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