ES2846183T3 - Métodos y composiciones farmacéuticas para el tratamiento de la infección por el virus de la hepatitis B - Google Patents
Métodos y composiciones farmacéuticas para el tratamiento de la infección por el virus de la hepatitis B Download PDFInfo
- Publication number
- ES2846183T3 ES2846183T3 ES14771231T ES14771231T ES2846183T3 ES 2846183 T3 ES2846183 T3 ES 2846183T3 ES 14771231 T ES14771231 T ES 14771231T ES 14771231 T ES14771231 T ES 14771231T ES 2846183 T3 ES2846183 T3 ES 2846183T3
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- Prior art keywords
- benzoimidazol
- phenyl
- acetamide
- chloro
- benzofuran
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Abstract
Un agonista del receptor farnesoide X (FXR) para usar en el tratamiento de la infección por el virus de la hepatitis B (VHB) en un sujeto que lo necesite, seleccionado del grupo que consiste en el compuesto identificado por el NÚMERO DE REGISTRO CAS 1192171-69-9, GW4064 de fórmula **(Ver fórmula)** y el ácido 6-etil-5 quenodesoxicólico **(Ver fórmula)** (6ECDCA) de fórmula
Description
DESCRIPCIÓN
Métodos y composiciones farmacéuticas para el tratamiento de la infección por el virus de la hepatitis B
La presente invención se refiere a métodos y composiciones farmacéuticas para el tratamiento de la infección por el virus de la hepatitis B.
Antecedentes de la invención
El VHB es un virus con envuelta que contiene un genoma de ADN parcialmente de doble cadena de 3,2 kb con cuatro marcos de lectura abiertos. Estos marcos de lectura abiertos codifican la transcriptasa inversa, proteínas pre-nucleares y nucleares; tres proteínas de antígeno de superficie (pre-S1, pre-S2 y S); y la proteína X. La regulación de la transcripción del VHB está bajo el control de cuatro promotores (los promotores del núcleo, de pre-S1, de pre-S2/S y de X) y dos regiones potenciadoras (EN1 y EN2). Se han determinado ocho genotipos del VHB, designados de la A a la H, con cierta distribución geográfica. El virus es no-citopático, siendo la inmunidad celular específica al virus el principal determinante del resultado de la exposición al VHB -infección aguda con resolución de las enfermedades hepáticas en 6 meses o infección crónica por VHB que se asocia frecuentemente con daño hepático progresivo. La detección de HBsAg en el suero mediante ensayos inmunológicos diagnósticos convencionales es el marcador diagnóstico clave de la infección por VHB y la detección persistente de HBsAg en suero durante más de 6 meses es el sello distintivo de la infección crónica por VHB. El mejor marcador para la replicación del VHB clínicamente significativa es el nivel de ADN del VHB en suero, como se detecta mediante el ensayo sensible basado en la reacción en cadena de la polimerasa (PCR). Más de 350 millones de personas en todo el mundo están infectadas de manera crónica con el VHB y, por lo tanto, tienen un mayor riesgo de desarrollar una enfermedad hepática grave, como hepatitis crónica, cirrosis, insuficiencia hepática y carcinoma hepatocelular (HCC).
El objetivo principal del tratamiento de la hepatitis B crónica (HBC) es suprimir de manera permanente la replicación del VHB y prevenir o mejorar la enfermedad hepática. Actualmente hay siete fármacos disponibles para el tratamiento de la infección de HBC: interferón convencional, interferón pegilado y agentes antivirales directos. Los antivirales directos (análogos de nucleós/(t)idos) pertenecen a tres clases: L-nucleósidos (lamivudina, telbivudina y emtricitabina); análogo de desoxiguanosina (entecavir) y fosfonatos de nucleósido (adefovir y tenofovir) que interfieren directamente con la replicación del ADN del VHB, principalmente como terminadores de cadena. Las limitaciones clave del tratamiento con interferón son los importantes efectos secundarios, la baja tasa de supresión del ADN del VHB y la baja tasa de normalización del la ALT; las limitaciones clave del tratamiento con antivirales directos son: desarrollo de resistencia; rebote de la replicación del VHB después de suspender el tratamiento que requiere un tratamiento prolongado de por vida, una tasa muy baja de aclaramiento del HBsAg, un aumento del riesgo de eventos adversos con la terapia prolongada de por vida. De manera importante, los antivirales directos actuales reprimen la transcripción inversa del ARN viral pre-genómico en ADN genómico. Por lo tanto, actúan corriente abajo hacia la formación del cccADN que se forma después de la entrada del virus en los hepatocitos. El cccADN reside en el núcleo celular como mini-cromosomas adicionales que se transcriben a ARNms virales y se transmiten a las células hijas cuando los hepatocitos se dividen. Los antivirales directos actuales tienen muy poco o ningún efecto sobre el reservorio de cccADN del VHB y la expresión de los genes virales. Por lo tanto, los actuales tratamientos disponibles no son óptimos y pueden estar asociados con efectos secundarios graves. Por consiguiente, existe la necesidad de mejores terapias para cumplir con los objetivos del tratamiento en la infección por VHB, en particular la infección HBC. Los antivirales que actúan de manera indirecta (IAD), además de los interferones, surgen como una clase alternativa muy prometedora de antivirales. Se han desarrollado con éxito pequeñas moléculas que bloquean la interacción de una proteína celular con una proteína viral para prevenir la entrada del VIH y de la replicación del VHC. La entrada viral y la inmunidad innata son funciones celulares obvias que se deben analizar para la identificación de nuevas dianas terapéuticas. Sin embargo, y a diferencia del VIH y del VHC, nuestro conocimiento de las funciones celulares específicas usadas por el VHB para replicarse en los hepatocitos sigue siendo muy limitado y es necesario un cribado sistemático para la identificación de estos factores esenciales del huésped para aumentar la diversidad de posibles dianas y moléculas terapéuticas potenciales. Por lo tanto, un objetivo principal es identificar estas funciones para prevenir su uso y/o perturbación por el virus mediante moléculas más seguras y de amplio espectro con alta barrera de resistencia.
Datos recientes sugieren fuertemente que el receptor farnesoide X (FXR), que es un miembro de la superfamilia de receptores nucleares, está implicado en la regulación de la actividad del promotor nuclear del VHB y que los ácidos biliares podrían desempeñar un papel importante e la historia natural de la infección por VHB (Ramiére C, Scholtés C, Diaz O, Icard V, Perrin-Cocon L, T rabaud MA, Lotteau V, André P. T ransactivation of the hepatitis B virus core promoter by the nuclear receptor FXRalpha. Journal of Virology, 2008; 82: 10832-10840). De manera específica, en el modelo celular particular de infección en la línea celular Huh-7 con varios vectores de infección de VHB, los datos sugieren que los agonistas del receptor FXRa aumentan la replicación viral mientras que los antagonistas de FXRa pueden representar una nueva clase de compuestos útiles para el tratamiento de la infección por VHB inhibiendo la replicación del VHB.
Resumen de la invención
El alcance de la presente invención está definido por las reivindicaciones y se proporciona cualquier información que no se encuentre dentro de las reivindicaciones únicamente a título informativo.
La presente descripción proporciona nuevos métodos para el tratamiento de pacientes con infecciones por el virus de la hepatitis B.
Descripción detallada de la invención.
La presente descripción se refiere a agonistas del receptor farnesoide X (FXR) para su uso en un método para el tratamiento de la infección por el virus de la hepatitis B en un sujeto que lo necesita.
Como se usa en esta memoria, un “paciente infectado con el virus de la Hepatitis B” quiere decir un paciente que está infectado con cualquier genotipo del virus de la hepatitis B, p. ej., genotipo A, B, C, D, etc.
De acuerdo con la descripción, el término “sujeto” o “paciente” y “sujeto que lo necesita” está dirigida a un mamífero humano o no humano infectado o con probabilidad de ser infectado con un virus de la hepatitis B. En algunos aspectos, el sujeto padece una infección por VHB crónica.
Como se usa en esta memoria, el término “tratamiento” o “tratar” se refiere tanto al tratamiento profiláctico o preventivo, así como al tratamiento curativo o modificador de la enfermedad, incluido el tratamiento del paciente en riesgo de contraer la enfermedad o que se sospecha que ha contraído la enfermedad, así como los pacientes que están enfermos o han sido diagnosticados que padecen una enfermedad o afección médica e incluye la supresión de recaída clínica. El tratamiento se puede administrar a un sujeto que tiene un trastorno médico o que finalmente puede adquirir el trastorno, con el fin de prevenir, curar, retrasar la aparición, reducir la gravedad o mejorar uno o más síntomas de un trastorno o trastorno recurrente, o con el fin de prolongar la supervivencia de un sujeto más allá de lo esperado en ausencia de dicho tratamiento. Por “régimen terapéutico” se entiende el patrón de tratamiento de una enfermedad, p. ej., el patrón de dosificación usado durante la terapia del VHB. Un régimen terapéutico puede incluir un régimen de inducción y un régimen de mantenimiento. La frase “régimen de inducción” o “periodo de inducción” se refiere a un régimen terapéutico (o la parte de un régimen terapéutico) que se usa para el tratamiento inicial de una enfermedad. El objetivo general de un régimen de inducción es proporcionar un alto nivel de fármaco a un paciente durante el periodo inicial de un régimen de tratamiento. Un régimen de inducción puede emplear (en parte o en su totalidad) un “régimen de carga”, que puede incluir administrar una dosis mayor del fármaco que la que emplearía un médico durante un régimen de mantenimiento, que administra un fármaco con más frecuencia de la que un médico administraría el fármaco durante un régimen de mantenimiento, o ambos. La frase “régimen de mantenimiento” o “periodo de mantenimiento” se refiere a un régimen terapéutico (o la parte de un régimen terapéutico) que se usa para el mantenimiento de un paciente durante el tratamiento de una enfermedad, p. ej., para mantener al paciente en remisión durante largos periodos de tiempo (meses o años). Un régimen de mantenimiento puede emplear terapia continua (p. ej., administrar un fármaco a intervalos regulares, p. ej., semanalmente, mensualmente, anualmente, etc.) o terapia intermitente (p. ej., tratamiento interrumpido, tratamiento intermitente, tratamiento en la recaída o tratamiento hasta lograr un criterio particular predeterminado [p. ej., dolor, manifestación de la enfermedad, etc.]).
La eficacia del régimen de terapia se puede monitorizar usando protocolos estándar. El tratamiento puede ir seguido de determinaciones de los niveles de VHB en suero y la medición de los niveles de ALT en suero. Por ejemplo, los pacientes pueden ser evaluados para detectar la presencia de ADN del VHB en sus sueros. El ADN del VHB (UI/ml) se puede medir a intervalos regulares durante el tratamiento, p. ej., en el Día 1 (antes de la dosis y 4, 8 y 12 horas después de la dosis) y antes de la dosis en el Día 2, Día 3, Día 8, Día 15, Día 29 y a la Semana 12, Semana 24, Semana 36, Semana 48, Semana 72 (cuando corresponda) y en el seguimiento. Por consiguiente, la eficacia de la terapia se controlará usando parámetros aceptados internacionalmente: a) Los niveles de ADN del VHB en suero usando ensayos cuantitativos sensibles basados en PCR para evaluar el efecto sobre la replicación viral. B) En pacientes HBeAg positivos, se monitoriza el HBeAg junto con el anti-HBe correspondiente para determinar si ha producido la seroconversión de HBe. C) Se controlan los niveles en suero de ALT y/o AST para el evaluar el impacto sobre la inflamación hepática y la muerte de las células hepáticas y d) Se controla e1HBsAg en suero cualitativa y cuantitativamente junto con los correspondientes anti-HBs para determinar si se ha producido la seroconversión de HBs ya que el aclaramiento de HBsAg y la seroconversión indicarían un resultado óptimo del tratamiento. En última instancia, incluso si no forma parte de la práctica clínica habitual, se podría evaluar la persistencia del cccADN mediante PCR específica para cuantificar el nivel de mini-cromosomas virales en biopsias hepáticas.
El término “FXR” se refiere al receptor farnesoide X, que es un receptor nuclear que se activa por niveles suprafisiológicos de farnesol (Forman y cols., Cell, 1995, 81, 687-693). El FXR, también se conoce como NR1H4, proteína 14 que interacciona con el receptor retinoide X (RIP14) el receptor de ácido biliar (BAR). El FXR, que contiene un dominio conservado de unión al ADN (DBD) y un dominio C-terminal de unión al ligando (LBD), se une y se activa por una variedad de ácidos biliares naturales (ABs), que incluyen el ácido biliar primario el ácido quenodesoxicólico (CDCA) y sus conjugados de taurina y glicina (Makishima y cols., 1999; Parks y cols., 1999; Wang y cols., 1999). Después de la activación, el heterodímero de FXR-RXR se une a la región promotora de los genes diana y regula la expresión de diversos genes implicados en la homeostasis de los ácidos biliares. Los genes diana del FXR hepático se dividen en dos grupos principales (Edwards PA. y cols., 2002, Kapadia SB. y cols. 2005). El primer grupo funciona para disminuir las concentraciones de los ácidos biliares hepáticos aumentando la exportación y disminuyendo su
síntesis. El segundo grupo de genes diana de FXR como la proteína transportadora de fosfolípidos PLTP y las apolipoproteínas modulan los niveles de lipoproteínas en el suero y disminuyen la concentración de triglicéridos en plasma. Para obtener una lista más detallada de genes regulados por FXR véase, p. ej., el documento WO 03/016288, páginas 22-23. La Patente de EE.UU. 6.005.086 describe la secuencia de ácido nucleico que codifica una proteína FXR de mamífero. Las secuencias polipeptídicas humanas de FXR están depositadas en las bases de datos de nucleótidos y proteína con los números de acceso NM_005123, Q96RI1, Np_005114 AAM53551, AAM53550, AAK60271.
En esta especificación, el término “agonista de FXR” tiene su significado general en la técnica y se refiere en particular a compuestos que funcionan dirigiéndose y uniéndose de manera selectiva al receptor farnesoide X (FXR) y que activa FXR en al menos un 40% por encima del fondo en el ensayo descrito por Maloney y cols. (J. Med. Chem. 2000, 43: 2971-2974).
En algunos aspectos, el agonista de FXR de la descripción es un agonista selectivo de FXR. Como se usa en esta memoria, el término “agonista selectivo de FXR” se refiere a un agonista de FXR que no exhibe reacción cruzada significativa con uno o mas, de manera ideal sustancialmente con todos, de un panel de receptores nucleares que consiste en LXRa, LXRp, PPARa, PPARg, PPAR8, RXRa, RARg, VDR, SXR, ERa, ERp, GR, AR, MR y PR. Los métodos para determinar la reacción cruzada significativa se describen en J. Med. Chem. 2009, 52, 904-907.
Los agonistas de FXR son bien conocidos por la persona experta en la técnica. Por ejemplo, la persona experta en la técnica puede identificar fácilmente el agonista de FXR a partir de las siguientes publicaciones:
- Adorini L, Pruzanski M, Shapiro D. Farnesoid X receptor targeting to treat nonalcoholic steatohepatitis. Drug Discov Today. 2012 Sep; 17 (17-18): 988-97. doi: 10.1016/j.drudis.2012.05.012. Epub 2012 May 29. Review.
- Akwabi-Ameyaw A, Bass JY, Caldwell RD, Caravella JA, Chen L, Creech KL, Deaton DN, Madauss KP, Marr HB, McFadyen RB, Miller AB, Navas F 3rd, Parks DJ, Spearing PK, Todd D, Williams SP, Bruce Wisely G. fXr agonist activity of conformationally constrained analogs of Gw 4064. Bioorg Med Chem Lett. 2009 Aug 15; 19(16): 4733-9. doi: 10.1016/j.bmcl.2009.06.062. Epub 2009 Jun 21.
- Akwabi-Ameyaw A, Bass JY, Caldwell RD, Caravella JA, Chen L, Creech KL, Deaton DN, Jones SA, Kaldor I, Liu Y, Madauss KP, Marr Hb , McFadyen RB, Miller AB, Iii FN, Parks DJ, Spearing PK, Todd D, Williams SP, Wisely GB. Conformationally constrained farnesoid X receptor (FXR) agonists: Naphthoic acid-based analogs of GW 4064. Bioorg Med Chem Lett. 2008 Aug 1; 18(15): 4339-43. doi: 10.1016/j.bmcl.2008.06.073. Epub 2008 Jun 28.
- Akwabi-Ameyaw A, Caravella JA, Chen L, Creech KL, Deaton DN, Madauss KP, Marr HB, Miller AB, Navas F 3rd, Parks DJ, Spearing PK, Todd D, Williams SP, Wisely GB. Conformationally constrained farnesoid X receptor (FXR) agonists: alternative replacements of the stilbene. Bioorg Med Chem Lett. 2011 Oct 15; 21(20): 6154-60. doi: 10.1016/j.bmcl.2011.08.034. Epub 2011 Aug 11.
- Baghdasaryan A, Claudel T, Gumhold J, Silbert D, Adorini L, Roda A, Vecchiotti S, Gonzalez FJ, Schoonjans K, Strazzabosco M, Fickert P, Trauner M. Dual farnesoid X receptor/TGR5 agonist INT-767 reduces liver injury in the Mdr2-/-(Abcb4-/-) mouse cholangiopathy model by promoting biliary HCO-3 output. Hepatology 2011 Oct; 54(4): 1303 12. doi: 10.1002/hep.24537.
- Bass JY, Caldwell RD, Caravella JA, Chen L, Creech KL, Deaton DN, Madauss KP, Marr HB, McFadyen RB, Miller AB, Parks DJ, Todd D, Williams SP, Wisely GB. Substituted isoxazole analogs of farnesoid X receptor (FXR) agonist GW4064. Bioorg Med Chem Lett. 2009 Jun 1; 19(11): 2969-73. doi: 10.1016/j.bmcl.2009.04.047. Epub 2009 Apr 18.
- Bass JY, Caravella JA, Chen L, Creech KL, Deaton DN, Madauss KP, Marr HB, McFadyen RB, Miller AB, Mills WY, Navas F 3rd, Smalley TL Jr, Spearing PK, Todd D, Williams SP, Wisely GB. Conformationally constrained farnesoid X receptor (FXR) agonists: heteroaryl replacements of the naphthalene. Bioorg Med Chem Lett. 2011 Feb 15; 21(4): 1206-13. doi: 10.1016/j.bmcl.2010.12.089. Epub 2010 Dec 23.
- Buijsman et al., Curr. Med. Chem. 2005, 12, 1017.
- Chiang PC, Thompson DC, Ghosh S, Heitmeier MR. A formulation-enabled preclinical efficacy assessment of a farnesoid X receptor agonist, GW4064, in hamsters and cynomolgus monkeys. J Pharm Sci. 2011 Nov; 100(11): 4722 33. doi: 10.1002/jps.22664. Epub 2011 Jun 9.
- Crawley, Expert Opin. Ther. Pat. 2010, 20, 1047.
- Feng S, Yang M, Zhang Z, Wang Z, Hong D, Richter H, Benson GM, Bleicher K, Grether U, Martin RE, Plancher JM, Kuhn B, Rudolph MG, Chen L. Identification of an N-oxide pyridine GW4064 analog as a potent FXR agonist. Bioorg Med Chem Lett. 2009 May 1; 19(9): 2595-8. doi: 10.1016/j.bmcl.2009.03.008. Epub 2009 Mar 9.
- Flatt B, Martin R, Wang TL, Mahaney P, Murphy B, Gu XH, Foster P, Li J, Pircher P, Petrowski M, Schulman I, Westin S, Wrobel J, Yan G, Bischoff E, Daige C, Mohan R. Discovery of XL335 (Wa Y-362450), a highly potent, selective, and
orally active agonist of the farnesoid X receptor (FXR). J Med Chem. 2009 Feb 26; 52(4): 904-7. doi: 10.1021 /jm8014124.
- Ghebremariam YT, Yamada K, Lee JC, Johnson CL, Atzler D, Anderssohn M, Agrawal R, Higgins JP, Patterson AJ, Boger RH, Cooke JP. FXR agonist INT-747 upregulates DDAH expression and enhances insulin sensitivity in high-salt fed Dahl rats. PLoS One. 2013 Apr 4; 8(4): e60653. doi: 10.1371/journal.pone.0060653. Print 2013.
- Gioiello A, Macchiarulo A, Carotti A, Filipponi P, Constantino G, Rizzo G, Adorini L, Pellicciari R. Extending SAR of bile acids as FXR ligands: discovery of 23-N-(carbocinnamyloxy)-3a,7a-dihydroxy-6 a-ethyl-24-nor-5p-cholan-23-amine. Bioorg Med Chem. 2011 Apr 15; 19(8): 2650-8. doi: 10.1016/j.bmc.2011.03.004. Epub 2011 Mar 10.
- Hoekstra M, van der Sluis RJ, Li Z, Oosterveer MH, Groen AK, Van Berkel TJ. FXR agonist GW4064 increases plasma glucocorticoid levels in C57BL/6 mice. Mol Cell Endocrinol. 2012 Oct 15; 362(1-2): 69-75. doi: 10.1016/j.mce.2012.05.010. Epub 2012 May 27.
- Iguchi Y, Kihira K, Nishimaki-Mogami T, Une M. Structure-activity relationship of bile alcohols as human farnesoid X receptor agonist. Steroids. 2010 Jan; 75(1): 95-100. doi: 10.1016/j.steroids.2009.11.002. Epub 2009 Nov 12.
- Lin HR. Triterpenes from Alisma orientalis act as farnesoid X receptor agonists. Bioorg Med Chem Lett. 2012 Jul 15; 22(14): 4787-92. doi: 10.1016/j.bmcl.2012.05.057. Epub 2012 May 23.
- Lefebvre P, Cariou B, Lien F, Kuipers F, Staels B. Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev. 2009 Jan; 89(1): 147-91. doi: 10.1152/physrev.00010.2008.
- Lundquist JT, Harnish DC, Kim CY, Mehlmann JF, Unwalla RJ, Phipps KM, Crawley ML, Commons T, Green DM, Xu W, Hum WT, Eta JE, Feingold I, Patel V, Evans MJ, Lai K, Borges-Marcucci L, Mahaney PE, Wrobel j E. Improvement of physiochemical properties of the tetrahydroazepinoindole series of farnesoid X receptor (FXR) agonists: beneficial modulation of lipids in primates. J Med Chem. 2010 Feb 25; 53(4): 1774-87. doi: 10.1021/jm901650u.
-Ma Y, Huang Y, Yan L, Gao M, Liu D. Synthetic FXR agonist GW4064 prevents diet-induced hepatic steatosis and insulin resistance. Pharm Res. 2013 May; 30(5): 1447-57. doi: 10.1007/s11095-013-0986-7. Epub 2013 Feb 1.
- Marinozzi M, Carotti A, Sardella R, Buonerba F, Ianni F, Natalini B, Passeri D, Rizzo G, Pellicciari R. Asymmetric synthesis of the four diastereoisomers of a novel non-steroidal farnesoid X receptor (FXR) agonist: Role of the chirality on the biological activity. Bioorg Med Chem. 2013 Jul 1; 21(13): 3780-9. doi: 10.1016/j.bmc.2013.04.038. Epub 2013 Apr 23.
- Misawa T, Hayashi H, Makishima M, Sugiyama Y, Hashimoto Y. E297G mutated bile salt export pump (BSEP) function enhancers derived from GW4064: structural development study and separation from farnesoid X receptor-agonistic activity. Bioorg Med Chem Lett. 2012 Jun 15; 22(12): 3962-6. doi: 10.1016/j.bmcl.2012.04.099. Epub 2012 Apr 30.
- Mudaliar S, Henry RR, Sanyal AJ, Morrow L, Marschall HU, Kipnes M, Adorini L, Sciacca CI, Clopton P, Castelloe E, Dillon P, Pruzanski M, Shapiro D. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology. 2013 Sep; 145(3): 574-82. e1. doi: 10.1053/j.gastro.2013.05.042. Epub 2013 May 30.
- Richter HG, Benson GM, Bleicher KH, Blum D, Chaput E, Clemann N, Feng S, Gardes C, Grether U, Hartman P, Kuhn B, Martin RE, Plancher JM, Rudolph MG, Schuler F, Taylor S. Optimization of a novel class of benzimidazolebased farnesoid X receptor (FXR) agonists to improve physicochemical and ADME properties. Bioorg Med Chem Lett.
2011 Feb 15; 21(4): 1134-40. doi: 10.1016/j.bmcl.2010.12.123. Epub 2010 Dec 31.
- Rizzo G, Passeri D, De Franco F, Ciaccioli G, Donadio L, Rizzo G, Orlandi S, Sadeghpour B, Wang XX, Jiang T, Levi M, Pruzanski M, Adorini L. Functional characterization of the semisynthetic bile acid derivative INT-767, a dual farnesoid X receptor and TGR5 agonist. Mol Pharmacol. 2010 Oct; 78(4): 617-30. doi: 10.1124/mol.110.064501. Epub 2010 Jul 14.
- Schuster D, Markt P, Grienke U, Mihaly-Bison J, Binder M, Noha SM, Rollinger JM, Stuppner H, Bochkov VN, Wolber G. Pharmacophore-based discovery of FXR agonists. Part I: Model development and experimental validation. Bioorg Med Chem. 2011 Dec 1; 19(23): 7168-80. doi: 10.1016/j.bmc.2011.09.056. Epub 2011 Oct 4.
- Soisson SM, Parthasarathy G, Adams AD, Sahoo S, Sitlani A, Sparrow C, Cui J, Becker JW. Identification of a potent synthetic FXR agonist with unexpected mode of binding and activation. Proc Natl Acad Sci U S A. 2008 Apr 8; 105(14): 5337-42. doi: 10.1073/pnas.0710981105. Epub 2008 Apr 7.
- Watanabe M, Horai Y, Houten SM, Morimoto K, Sugizaki T, Arita E, Mataki C, Sato H, Tanigawara Y, Schoonjans K, Itoh H, Auwerx J. Lowering bile acid pool size with a synthetic farnesoid X receptor (FXR) agonist induces obesity and diabetes through reduced energy expenditure. J Biol Chem. 2011 Jul 29; 286(30): 26913-20. doi: 10.1074/jbc.M111.248203. Epub 2011 Jun 1.
- Yu D, Mattern DL, Forman BM. An improved synthesis of 6a-ethylchenodeoxycholic acid (6ECDCA), a potent and selective agonist for the Farnesoid X Receptor (FXR). Steroids. 2012 Nov; 77(13): 1335-8. doi: 10.1016/j.steroids.2012.09.002. Epub 2012 Sep 21.
- Zhang S, Wang J, Liu Q, Harnish DC. Farnesoid X receptor agonist WAY-362450 attenuates liver inflammation and fibrosis in murine model of non-alcoholic steatohepatitis. J Hepatol. 2009 Aug; 51(2): 380-8. doi: 10.1016/j.jhep.2009.03.025. Epub 2009 May 18.
Normalmente los agonistas de FXR incluyen la clase de agonistas esteroideos de FXR y de agonistas no esteroideos de FXR.
En ciertos aspectos de la descripción, el agonista de FXR se selecciona de compuestos de moléculas pequeñas que actúan como moduladores de FXR que se han descrito en las siguientes publicaciones:
EP1392714;
EP1568706;
EP2128158;
EP2289883;
JP2005281155;
US20030203939;
US2005080064;
US2006128764;
US20070010562;
US20070015796;
US20080038435;
US20080300235;
US20090062526;
US20090163552;
US20100093818;
US20100184809;
US20110077273;
US20110105475;
US6984560;
US7671085;
WO2000037077;
WO200040965;
WO200076523;
WO2001017994;
WO2003015771;
WO2003016280;
WO2003016288;
WO2003030612;
WO2003060078;
WO2003080803;
WO2003090745;
WO2004007521;
WO2004046162;
WO2004048349;
WO2005082925;
WO2005092328;
WO2005097097;
WO2006020680;
WO2007076260;
WO2007076260;
WO2007092751;
WO2007140174;
WO2007140183;
WO2008000643;
WO2008002573;
WO2008025539;
WO2008025540;
WO2008051942;
WO2008073825;
WO2008157270;
WO2009005998;
WO2009012125;
WO2009027264;
WO2009062874;
WO2009080555;
WO2009127321;
WO2009149795;
WO2010028981;
WO2010034649;
WO2010034657;
WO2010069604;
WO2011020615;
WO2013007387;
y WO2013037482.
Los ejemplos específicos de agonistas de FXR incluyen, pero no se limitan a, GW4064 (como se describe en la publicación PCT N°. WO 00/37077 o en la US2007/0015796), ácidos 6-etil-quenodesoxicólicos (6ECDCA),
especialmente ácido 3a, 7 a-dihidroxi 7 a-dihidroxi-6 a-etil-5p-colan-24-oico, también denominado INT-747; ácidos 6-etil-ursodesoxicólicos, INT-1103, UPF-987, WAY-362450, MFA-1, GW9662, T0901317, fexaramina, un ácido cólico, un ácido desoxicólico, un ácido glicocólico, un ácido glicodesoxicólico, un ácido taurocólico, un taurodihidrofusidato, un ácido taurodesoxicólico, un colato, un glicocolato, un desoxicolato, un taurocolato, un taurodesoxicolato, un ácido quenodesoxicólico, un ácido 7-B-metil cólico, un ácido metil litocólico.
En algunos aspectos, el agonista de FXR no se selecciona de ácidos biliares naturales, preferiblemente ácido quenodesoxicólico [CDCA] o CDCA conjugado con taurina o glicina [tauro-CDCA o glico-CDCA] y derivados sintéticos de ácidos biliares naturales, preferiblemente 6-Etil-CDCA o 6-Etil-CDCA conjugado con taurina o glicina, agonistas no esteroideos naturales, preferiblemente Diterpenoides como Cafestol y Kahweol, o agonistas de FXR no esteroideos sintéticos.
En algunos aspectos, el agonista de FXR se selecciona del grupo que consiste en GW4064, 6ECDCA y el compuesto identificado por el NÚMERO DE REGISTRO CAS 1192171-69-9 (descrito en el documento WO 2009127321 también llamado PXL007):
En algunos aspectos, el agonista de FXR es el compuesto que tiene la fórmula de:
En algunos aspectos, el agonista de FXR es el compuesto que tiene la fórmula de:
En algunos aspectos, el agonista de FXR es el compuesto que tiene la fórmula de:
En algunos aspectos, el agonista de FXR se selecciona del grupo que consiste en:
En algunos aspectos, el agonista de FXR se selecciona del grupo que consiste en los compuestos descritos en el documento WO2013007387, es decir:
En algunos aspectos, el agonista de FXR se selecciona del grupo que consiste en los compuestos descritos en el documento w O2011020615, es decir:
ácido 3-(2-(2-cloro-4-((5-ciclopropil-3-(2,6-diclorofenil)isoxazol-4-il)metoxi)fenil)ciclopropil)benzoico
ácido (-)-3-(2-(2-cloro-4-((5-ciclopropil-3-(2,6-diclorofenil)isoxazol-4-il)metoxi)fenil)ciclopropil)benzoico
ácido (+)-3-(2-(2-cloro-4-((5-ciclopropil-3-(2,6-diclorofenil)isoxazol-4-il)metoxi)fenil)ciclopropil)benzoico
ácido 3-(2-(2-cloro-4-((3-(2,6-diclorofenil)-5-isopropilisoxazol-4-il)metoxi)fenil)ciclopropil)benzoico
ácido 3-(2-(2-cloro-4-((5-ciclopropil-3-(3,5-dicloropiridin-4-il)isoxazol-4-il)metoxi)fenil)ciclopropil)benzoico óxido de 4-(4-((4-(2-(3-carboxifenil)ciclopropil)-3-clorofenoxi)metil)-5-ciclopropilisoxazol-3-il)-3,5-dicloropiridina 1 ácido 3-(2-(2-cloro-4-((1 -(2,6-diclorofenil)-4-isopropil-1 H-1,2,3-triazol-5-il)metoxi)fenil)ciclopropil)benzoico
4-((4-(2-(6-(1 /-/-tetrazol-5-il)piridin-3-il)ciclopropil)-3-clorofenoxi)metil)-5-ciclopropil-3-(2,6-diclorofenil)isoxazol ácido 5-(2-(2-cloro-4-((5-cloropropil-3-(2,6-diclorofenil)isoxazol-4-il)metoxi)fenil)ciclopropil)picolínico
ácido 4-(2-(2-cloro-4-((5-cloropropil-3-(2,6-diclorofenil)isoxazol-4-il)metoxi)fenil)ciclopropil)benzoico
4-(2-(2-cloro-4-((5-ciclopropil-3-(2,6-diclorofenil)isoxazol-4-il)metoxi)fenil)ciclopropil)benzoato de 1,3-dihidroxi-2-(hidroximetil)propan-2-aminio
ácido (+)-4-(2-(2-cloro-4-((5-ciclopropil-3-(2,6-diclorofenil)isoxazol-4-il)metoxi)fenil)ciclopropil)benzoico
ácido (-)-4-(2-(2-cloro-4-((5-ciclopropil-3-(2,6-diclorofenil)isoxazol-4-il)metoxi)fenil)ciclopropil)benzoico
ácido 6-(2-(2-cloro-4-((5-ciclopropil-3-(2,6-diclorofenil)isoxazol-4-il)metoxi)fenil)ciclopropil)-1-metil-1 H-indazol-3-carboxílico
ácido (+)-6-(2-(2-cloro-4-((5-ciclopropil-3-(2,6-diclorofenil)isoxazol-4-il)metoxi)fenil)ciclopropil)-i-metil-1 H-indazol-3-carboxílico
ácido (-)-6-(2-(2-cloro-4-((5-ciclopropil-3-(2,6-diclorofenil)isoxazol-4-il)metoxi)fenil)ciclopropil)-1-metil-1 H-indazol-3-carboxílico
4-(2-(2-cloro-4-((5-ciclopropil-3-(2,6-diclorofenil)isoxazol-4-il)metoxi)fenil)ciclopropil)-N-(metilsulfonil)benzamida ácido 2-(4-(2-(2-cloro-4-((5-ciclopropil-3-(2,6-diclorofenil)isoxazol-4-il)metoxi)fenil)ciclopropil)benzamido)etanosulfónico
4-((4-(2-(4-(1 H-tetrazol-5-il)fenil)ciclopropil)-3-clorofenoxi)metil)-5-ciclopropil-3-(2,6-diclorofenil)isoxazol
ácido 4-(2-(2-cloro-4-((3-(2,6-diclorofenil)-5-(2-hidroxipropan-2-il)isoxazol-4-il)metoxi)fenil)ciclopropil)benzoico
ácido 5-(2-(2-cloro-4-((5-ciclopropil-3-(2,6-diclorofenil)isoxazol-4-il)metoxi)fenil)ciclopropil)-1-isopropil-1 H-pirazol-3-carboxílico
ácido 6-(2-(2-cloro-4-((5-ciclopropil-3-(2,6-diclorofenil)isoxazol-4-il)metoxi)fenil)ciclopropil)-i-isopropil-1 H-indazol-3-carboxílico
ácido 4-(2-(2-cloro-4-((5-ciclopropil-3-(2,6-diclorofenil)isoxazol-4-il)metoxi)fenil)ciclopropil)-2,6-dimetilbenzoico ácido 4-(2-(2-cloro-4-((5-ciclopropil-3-(2-trifluorometoxi)fenil)isoxazol-4-il)metoxi)fenil)ciclopropil)benzoico ácido (+)-2-(4-(2-(2-cloro-4-((5-ciclopropil-3-(2,6-diclorofenil)isoxazol-4-il)metoxi)fenil)ciclopropil)benzamido)etanosulfónico
ácido 2-(4-(2-(2-cloro-4-((5-ciclopropil-3-(2,6-diclorofenil)isoxazol-4-il)metoxi)fenil)ciclopropil)benzamido)acético y ácido 4-(2-(2-cloro-4-((4-(2,6-diclorofenil)-1 -isopropil-1 H-1,2,3-triazol-5-il)metoxi)fenil)ciclopropil)benzoico
En algunos aspectos, el agonista de FXR se selecciona del grupo que consiste en los compuestos descritos en el documento WO2009149795, es decir:
En algunos aspectos, el agonista de FXR se selecciona del grupo que consiste en los compuestos descritos en el documento WO2008025539, es decir:
En algunos aspectos, el agonista de FXR se selecciona del grupo que consiste en los compuestos descritos en el documento WO2008025540, es decir:
En algunos aspectos, el agonista de FXR se selecciona del grupo que consiste en los compuestos descritos en el documento WO2009127321, es decir:
éster terc-butílico del ácido 4-(4-Bromo-2-etoxicarbonil-benzofuran-5-il)-piperazin-1 -carboxílico
éster terc-butílico del ácido 4-(4-Bromo-2-carboxi-benzofuran-5-il)-piperazin-1 -carboxílico
éster terc-butílico del ácido 4-(2-Carboxi-benzofuran-5-il)-piperazin-1-carboxílico
amida del ácido 5-[4-(3-Metoxi-bencenosulfonil)-piperazin-1-il]-benzofuran-2-carboxílico
amida del ácido 5-[4-(4-Metoxi-bencenosulfonil)-piperazin-1-il]-benzofuran-2-carboxílico
éster terc-butílico del ácido 4-(2-Etoxicarbonil-benzofuran-5-il)-piperazin-1-carboxílico
amida del ácido 5-[4-(3-T rifluorometil-bencil)-piperazin-1 -il]-benzofuran-2-carboxílico
amida del ácido 5-[4-(3-Cloro-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
amida del ácido 5-[4-(3-Fluoro-bezoil)-piperazin-1-il]-benzofuran-2-carboxílico
amida del ácido 4-Bromo-5-[4-(4-metoxi-bencenosulfonil)-piperazin-1 -il]-benzofuran-2-carboxílico
ácido 5-(4-Bencenosulfonil-piperazin-1-il)-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(3-fluoro-benzoil)-piperazin-1 -il]-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(3-cloro-bencenosulfonil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(3-fluoro-bencenosulfonil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(pirrolidin-1 -carbonil)-piperazin-1 -il]-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(3-cloro-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
éster terc-butílico del ácido 4-(2-Carboxi-benzofuran-5-ilamino)-piperidin-1-carboxílico
éster terc-butílico del ácido 2-[4-(4-Bromo-2-carboxi-benzofuran-5-il)-piperazin-1 -carbonil]-pirrolidin-1 -carboxílico éster terc-butílico del ácido 4-(4-Cloro-2-etoxicarbonil-benzofuran-5-il)-piperazin-1 -carboxílico
éster terc-butílico del ácido 4-(2-Carboxi-4-cloro-benzofuran-5-il)-piperazin-1-carboxílico
ácido 5-(4-Bencil-piperazin-1 -il)-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(3-trifluorometil-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 5-[4-(3-Metoxi-bencenosulfonil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(3-metoxi-bencenosulfonil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(4-metoxi-bencenosulfonil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(pirrolidin-2-carbonil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 5-[4-(Adamantan-1 -carbonil)-piperazin-1 -il]-4-bromo-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(3-cloro-benzoil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(2-fluoro-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(3-fluoro-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 5-(4-Benzoil-piperazin-1-il)-4-bromo-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(3-trifluorometil-benciloxi)-piperidin-1-il]-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(3-cloro-benciloxi)-piperidin-1-il]-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(2-cloro-bencenosulfonil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(4-cloro-bencenosulfonil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(4-fluoro-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(2-cloro-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(4-cloro-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(piridin-2-iloxi)-piperidin-1-il]-benzofuran-2-carboxílico
amida del ácido 4-Bromo-5-[4-(3-trifluorometil-bencil)-piperazin-1 -il]-benzofuran-2-carboxílico
amida del ácido 5-[4-(3-Trifluorometoxi-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
amida del ácido 4-Bromo-5-[4-(3-trifluorometoxi-bencil)-piperazin-1 -il]-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(3-ciano-bencenosulfonil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Bromo-5-(4-terc-butilcarbamoil-piperazin-1-il)-benzofuran-2-carboxílico
amida del ácido 4-Bromo-5-[4-(3-fluoro-bencenosulfonil)-piperazin-1 -il]-benzofuran-2-carboxílico
amida del ácido 4-Bromo-5-[4-(3,5-dicloro-benzoil)-piperazin-1-il]-benzofuran-2-carboxílico
amida del ácido 4-Bromo-5-[4-(3,5-difluoro-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Bromo-5-(4-piridin-3-ilmetil-piperazin-1-il)-benzofuran-2-carboxílico
ácido 4-Bromo-5-(4-piridin-4-ilmetil-piperazin-1-il)-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(3-trifluorometoxi-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(3-fenoxi-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(3,5-dimetoxi-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 5-[4-(3-Alil-2-hidroxi-bencil)-piperazin-1-il]-4-bromo-benzofuran-2-carboxílico
ácido 5-(4-Bencenosulfonil-piperazin-1-il)-4-bromo-benzofuran-2-carboxílico
ácido 4-Bromo-5-(4-terc-butilcarbamoil-piperidin-1-il)-benzofuran-2-carboxílico
ácido 4-Cloro-5-[4-(2-cloro-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Cloro-5-[4-(3-cloro-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Cloro-5-[4-(4-cloro-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Cloro-5-[4-(2-fluoro-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Cloro-5-[4-(3-fluoro-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Cloro-5-[4-(4-fluoro-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Cloro-5-[4-(3-trifluorometil-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Cloro-5-[4-(3-trifluorometoxi-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 5-[4-(3-Carboxi-bencil)-piperazin-1-il]-4-cloro-benzofuran-2-carboxílico
ácido 4-Cloro-5-(4-piridin-3-ilmetil-piperazin-1-il)-benzofuran-2-carboxílico
ácido 4-Cloro-5-[4-(2-cloro-bencenosulfonil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Cloro-5-[4-(3-cloro-bencenosulfonil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Cloro-5-[4-(4-cloro-bencenosulfonil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Cloro-5-[4-(4-metoxi-bencenosulfonil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Cloro-5-[4-(3-metoxi-bencenosulfonil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Cloro-5-[4-(3-fluoro-benzoil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Cloro-5-[4-(3,5-dicloro-benzoil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Cloro-5-[4-(3-fluoro-bencenosulfonil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Cloro-5-[4-(3-ciano-bencenosulfonil)-piperazin-1-il]-benzofuran-2-carboxílico
amida del ácido 4-Bromo-5-[4-(2-cloro-bencenosulfonil)-piperazin-1 -il]-benzofuran-2-carboxílico etoxi-amida del ácido 4-Bromo-5-[4-(3-fluoro-bencenosulfonil)-piperazin-1 -il]-benzofuran-2-carboxílico ácido 4-Bromo-5-[4-(3-trifluorometil-benzoil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(3-trifluorometoxi-benzoil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(3-metoxi-benzoil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(2,5-dicloro-benzoil)-piperazin-1 -il]-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(3,5-dicloro-benzoil)-piperazin-1 -il]-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(2-metil-1H-benzoimidazol-4-carbonil)-piperazin-1-il]-benzofuran-2-carboxílico ácido 4-Bromo-5-[4-(5-trifluorometil-piridin-2-iloxi)-piperidin-1-il]-benzofuran-2-carboxílico ácido 4-Cloro-5-[4-(3-cloro-benzoil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Cloro-5-[4-(2,5-dicloro-benzoil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Cloro-5-[4-(3-metoxi-benzoil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Cloro-5-[4-(3-trifluorometil-benzoil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Cloro-5-[4-(3-trifluorometoxi-benzoil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Cloro-5-[4-(2-metil-1 H-benzoimidazol-4-carbonil)-piperazin-1-il]-benzofuran-2-carboxílico ácido 5-[4-(1 H-benzoimidazol-5-carbonil)-piperazin-1 -il]-4-cloro-benzofuran-2-carboxílico
ácido 4-Cloro-5-[4-(2,5-dicloro-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Cloro-5-[4-(3,5-dimetoxi-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Cloro-5-[4-(3-cloro-fenilmetanosulfonil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 5-[4-(2-Cloro-bencenosulfonil)-piperazin-1-il]-4-metil-benzofuran-2-carboxílico
ácido 5-[4-(3-Fluoro-bencenosulfonil)-piperazin-1-il]-4-metil-benzofuran-2-carboxílico
éster terc-butílico del ácido 4-(2-Carboxi-4-metil-benzofuran-5-il)-piperazin-1-carboxílico
éster terc-butílico del ácido 4-(2-Carboxi-4-cloro-benzofuran-5-il)-[1,4] diazepan-1-carboxílico
éster terc-butílico del ácido 4-(4-Bromo-2-carboxi-benzofuran-5-il)-[1,4] diazepan-1-carboxílico
ácido 4-Bromo-5-[4-(2-cloro-bencenosulfonil)-[1,4] diazepan-1 -il]-benzofuran-2-carboxílico
ácido 4-Cloro-5-[4-(2-cloro-bencenosulfonil)-[1,4] diazepan-1 -il]-benzofuran-2-carboxílico
ácido 4-Cloro-5-[4-(5-trifluorometil-piridin-2-iloxi)-piperidin-1-il]-benzofuran-2-carboxílico
ácido 4-Bromo-5-[1-(3-cloro-bencenosulfonil)-piperidin-4-ilamino]-benzofuran-2-carboxílico
{4-Bromo-5-[4-(2-cloro-bencenosulfonil)-piperazin-1-il]-benzofuran-2-il}-morfolin-4-il-metanona
(2-metoxi-etil)-amida del ácido 4-bromo-5-[4-(2-cloro-bencenosulfonil)-piperazin-1 -il]-benzofuran-2-carboxílico ácido 4-Bromo-5-[4-(2,5-dicloro-bencenosulfonil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(2,5-dicloro-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 5-[4-(1 H-Benzoimidazol-5-carbonil)-piperazin-1 -il]-4-bromo-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(2,6-dicloro-benzoil)-piperazin-1 -il]-benzofuran-2-carboxílico
ácido 5-[4-(2,6-Dicloro-benzoil)-piperazin-1-il]-4-metil-benzofuran-2-carboxílico
ácido 5-[4-(2,5-Dicloro-benzoil)-piperazin-1-il]-4-metil-benzofuran-2-carboxílico
ácido 4-Metil-5-[4-(3-trifluorometoxi-benzoil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 5-[4-(2-Cloro-bencil)-piperazin-1-il]-4-metil-benzofuran-2-carboxílico
ácido 5-[4-(3-Cloro-bencil)-piperazin-1-ilH-metil-benzofuran-carboxílico
ácido 5-[4-(2,5-Dicloro-bencil)-piperazin-1-il]-4-metil-benzofuran-2-carboxílico
ácido 5-[4-(3-Fluoro-bencil)-piperazin-1-il]-4-metil-benzofuran-2-carboxílico
ácido 4-Metil-5-[4-(3-trifluorometil-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Metil-5-[4-(3-trifluorometoxi-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 5-[4-(3-Cloro-bencenosulfonil)-piperazin-1-il]-4-metil-benzofuran-2-carboxílico
ácido 5-[4-(2,5-Dicloro-bencenosulfonil)-piperazin-1-il]-4-metil-benzofuran-2-carboxílico
ácido 5-[4-(3-Cloro-fenilmetanosulfonil)-piperazin-1-il]-4-metil-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(2-cloro-6-fluoro-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Cloro-5-[4-(2-cloro-6-fluoro-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(3-cloro-fenilmetanosulfonil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Cloro-5-[1-(3-cloro-bencenosulfonil)-piperidin-4-ilamino]-benzofuran-2-carboxílico
ácido 4-Bromo-5-(3,4-dihidro-1 H-isoquinolin-2-il)-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(3-cloro-fenoxi)-piperidin-1-il]-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(4-trifluorometil-pirimidin-2-iloxi)-piperidin-1-il]-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(2-fluoro-bencenosulfonil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 5-[4-(2-Fluoro-bencenosulfonil)-piperazin-1-il]-4-metil-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(2,6-dicloro-bencenosulfonil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 5-[4-(2,6-Dicloro-bencenosulfonil)-piperazin-1-il]-4-metil-benzofuran-2-carboxílico
ácido 4-Cloro-5-[4-(2,6-dicloro-bencenosulfonil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(2,3-dicloro-bencenosulfonil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 5-[4-(2,3-Dicloro-bencenosulfonil)-piperazin-1-il]-4-metil-benzofuran-2-carboxílico
ácido 4-Cloro-5-[4-(2,3-dicloro-bencenosulfonil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Cloro-5-[4-(2,5-dicloro-bencenosulfonil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(2,3-dicloro-benzoil)-piperazin-1 -il]-benzofuran-2-carboxílico
ácido 4-Metil-5-[4-(3-trifluorometil-benzoil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Metil-5-[4-(2-metil-1 H-benzoimidazol-4-carbonil)-piperazin-1-il]-benzofuran-2-carboxílico ácido 5-[4-(2-Fluoro-bencil)-piperazin-1-il]-4-metil-benzofuran-2-carboxílico
ácido 5-[4-(2-Cloro-6-fluoro-bencil)-piperazin-1-il]-4-metil-benzofuran-2-carboxílico
ácido 5-[4-(2,6-Dicloro-bencil)-piperazin-1-il]-4-metil-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(3,5-dicloro-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 5-[4-(3,5-Dicloro-bencil)-piperazin-1-il]-4-metil-benzofuran-2-carboxílico
ácido 4-Cloro-5-[4-(3,5-dicloro-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 5-[4-(3-Alil-2-hidroxi-bencil)-piperazin-1-il]-4-metil-benzofuran-2-carboxílico
ácido 5-[4-(2,3-Dimetoxi-bencil)-piperazin-1-il]-4-metil-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(5-cloro-tiofen-2-ilmetil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Metil-5-[4-(5-trifluorometil-piridin-2-iloxi)-piperidin-1-il]-benzofuran-2-carboxílico
éster terc-butílico del ácido 4-(2-Carboxi-4-ciano-benzofuran-5-il)-piperazin-1-carboxílico
ácido 4-Bromo-5-[4-(4-cloro-fenoxi)-piperidin-1-il]-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(3-etoxi-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
bencilamida del ácido 4-Bromo-5-[4-(2-cloro-bencenosulfonil)-piperazin-1 -il]-benzofuran-2-carboxílico ácido 5-(Benzo[1,3]dioxol-4-ilmetil-piperazin-1 -il)-4-bromo-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(2,6-dicloro-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(2,4-dicloro-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 5-[4-(2-Aliloxi-bencil)-piperazin-1-il]-4-bromo-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(3-trifluorometil-fenoxi)-piperidin-1-il]-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(4-trifluorometil-fenoxi)-piperidin-1-il]-benzofuran-2-carboxílico
ácido 4-Bromo-5-{4-[ciclopropanocarbonil-(2,4-dicloro-fenil)-amino]-piperidin-1-il}-benzofuran-2-carboxílico ácido 4-Bromo-5-{4-[(4-cloro-bencil)-ciclopropanocarbonil-amino]-piperidin-1-il}-benzofuran-2-carboxílico ácido 5-{4-[3-(2,6-Dicloro-fenil)-5-isopropil-isoxazol-4-carbonil]-piperazin-1-il}-4-metil-benzofuran-2-carboxílico ácido 4-Bromo-5-[4-(2-trifluorometil-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 5-[4-(3-Aliloxi-bencil)-piperazin-1-il]-4-bromo-benzofuran-2-carboxílico
ácido 5-[4-(3-Alil-2-metoxi-bencil)-piperazin-1-il]-4-metil-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(3-terc-butil-2-hidroxi-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Metil-5-(4-naftalen-1 -ilmetil-piperazin-1 -il)-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(2-hidroxi-naftalen-1 -ilmetil)-piperazin-1 -il]-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(2-trifluorometil-bencenosulfonil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(3-trifluorometil-bencenosulfonil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(2,6-dicloro-bencenosulfonil)-[1,4]diazepan-1-il]-benzofuran-2-carboxílico
{4-Bromo-5-[4-(2,6-dicloro-bencenosulfonil)-[1 I4]diazepan-1-il]-benzofuran-2-il}-morfolin-4-il-metanona
{4-Bromo-5-[4-(2,6-dicloro-bencenosulfonil)-[1,4]diazepan-1-il]-benzofuran-2-il}-piperidin-1-il-metanona
{5-[4-(3,5-Dicloro-2-hidroxi-bencenosulfonil)-piperazin-1-il]-4-metil-benzofuran-2-il}-morfolin-4-il-metanona
{4-Bromo-5-[4-(2-fluoro-bencenosulfonil)-piperazin-1-il]-benzofuran-2-il}-morfolin-4-il-metanona
{4-Bromo-5-[4-(2-cloro-bencenosulfonil)-piperazin-1-il]-benzofuran-2-il}-piperidin-1-il-metanona
{4-Bromo-5-[4-(2,6-dicloro-bencenosulfonil)-piperazin-1-il]-benzofuran-2-il}-piperidin-1-il-metanona
{4-Bromo-5-[4-(2,6-dicloro-bencenosulfonil)-piperazin-1-il]-benzofuran-2-il}-morfolin-1-il-metanona
ácido 4-Bromo-5-[4-(2,6-dicloro-benzoil)-[1,4]diazepan-1 -il]-benzofuran-2-carboxílico
ácido 5-[4-(3-Alil-2-hidroxi-bencil)-[1,4]diazepan-1 -il]-4-bromo-benzofuran-2-carboxílico
ácido 5-[4-(3,5-Dicloro-2-hidroxi-bencil)-piperazin-1-il]-4-metil-benzofuran-2-carboxílico
ácido 4-Metil-5-[4-(2,3,6-tricloro-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 5-[4-(2,3-Dicloro-bencil)-piperazin-1-il]-4-metil-benzofuran-2-carboxílico
ácido 4-Bromo-5-{4-[4-bromo-5-(4-fluoro-2-metoxi-fenil)-3-metil-pirazol-1-il]-piperidin-1-il}-benzofuran-2-carboxílico ácido 4-Bromo-5-(4-{[4-cloro-bencil)-ciclopropilmetil-amino]-metil}-piperidin-1-il)-benzofuran-2-carboxílico
{4-Bromo-5-[4-(2,6-dicloro-benzoil)-[1,4]diazepan-1-il]-benzofuran-2-il}-morfolin-4-il-metanona
ácido 4-Cloro-5-[4-(2,6-dicloro-benzoil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Cloro-5-[1-(2,6-dicloro-bencenosulfonil)-piperidin-4-ilamino]-benzofuran-2-carboxílico
{4-Cloro-5-[4-(2,3-dicloro-bencenosulfonil)-piperazin-1-il]-benzofuran-2-il}-morfolin-4-il-metanona
{4-Bromo-5-[4-(2,6-dicloro-bencenosulfonil)-piperazin-1-il]-benzofuran-2-il}-(4-metil-piperazin-1-il)-metanona (2-dimetilamino-etil)-amida del ácido 4-bromo-5-[4-(2,6-dicloro-bencenosulfonil)-piperazin-1 -il]-benzofuran-2-carboxílico
ácido 4-Cloro-5-[4-(2-hidroxi-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
{5-[4-(2,6-Dicloro-bencil)-piperazin-1-il]-4-metil-benzofuran-2-il}-morfolin-4-il-metanona
ácido 4-Cloro-5-[4-(2,6-dicloro-bencenosulfonil)-[1,4]diazepan-1-il]-benzofuran-2-carboxílico
ácido 5-[4-(2,3-Dicloro-bencenosulfonil)-[1,4]diazepan-1-il]-4-metil-benzofuran-2-carboxílico
{5-[4-(2,3-Dicloro-bencenosulfonil)-[1,4]diazepan-1-il]-4-metil-benzofuran-2-il}-morfolin-4-il-metanona
ácido 4-Cloro-5-[4-(2,3-dicloro-bencenosulfonil)-[1,4]diazepan-1-il]-benzofuran-2-carboxílico
{4-Cloro-5-[4-(2,3-dicloro-bencenosulfonil)-[1,4]diazepan-1-il]-benzofuran-2-il}-morfolin-4-il-metanona
ácido 4-Cloro-5-[4-(2,5-dicloro-bencenosulfonil)-[1,4]diazepan-1-il]-benzofuran-2-carboxílico
{4-Cloro-5-[4-(2,5-dicloro-bencenosulfonil)-[1,4]diazepan-1-il]-benzofuran-2-il}-morfolin-4-il-metanona
ácido 5-[4-(2,5-Dicloro-bencenosulfonil)-[1,4]diazepan-1-il]-4-metil-benzofuran-2-carboxílico
{5-[4-(2,5-Dicloro-bencenosulfonil)-[1,4]diazepan-1-il]-4-metil-benzofuran-2-il}-morfolin-4-il-metanona
{4-Cloro-5-[4-(2,6-dicloro-bencenosulfonil)-[1,4]diazepan-1-il]-benzofuran-2-il}-morfolin-4-il-metanona
ácido 4-Cloro-5-[4-(2-cloro-6-hidroxi-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Cloro-5-[4-(2-cloro-6-metoxi-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Cloro-5-[4-(3-etoxi-2-hidroxi-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 4-Cloro-5-[4-(2-cloro-3-trifluorometil-bencil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 5-{4-[3-(2,6-Dicloro-fenil)-5-isopropil-isoxazol-4-ilmetil]-piperazin-1-il}-4-metil-benzofuran-2-carboxílico amida del ácido 5-[4-(2,6-Dicloro-bencil)-piperazin-1-il]-4-metil-benzofuran-2-carboxílico
ácido 5-[4-(2,6-Dicloro-bencil)-[1,4]diazepan-1 -il]-4-metil-benzofuran-2-carboxílico
{5-[4-(2,6-Dicloro-bencil)-[1,4]diazepan-1-il]-4-metil-benzofuran-2-il}-(4-metil-piperazin-1-il)-metanona
{4-Bromo-5-[4-(2,6-dicloro-benzoil)-[1,4]diazepan-1-il]-benzofuran-2-il}-piperidin-1-il-metanona
ácido 4-Bromo-5-[1-(2,6-dicloro-benzoil)-piperidin-4-ilamino]-benzofuran-2-carboxílico
ácido 4-Bromo-5-[1-(2,3-dicloro-benzoil)-piperidin-4-ilamino]-benzofuran-2-carboxílico
ácido 4-Cloro-5-[4-(2,3-dihidro-indol-1 -il)-piperidin-1 -il]-benzofuran-2-carboxílico
éster terc-butílico del ácido 4-[2-(1Htetrazol-5-il)-benzofuran-5-il]-piperazin-1-carboxílico
ácido 5-(4-Bencidril-piperazin-1-il)-4-metil-benzofuran-2-carboxílico
ácido 4-Bromo-5-[4-(2,6-dicloro-bencenosulfonilamino)-piperidin-1-il]-benzofuran-2-carboxílico
ácido 4-Cloro-5-[4-(2-metil-5-tiofen-2-il-2H-pirazol-3-ilmetil)-piperazin-1-il]-benzofuran-2-carboxílico
ácido 5-[(1S,4S)-5-(2,6-Dicloro-bencenosulfonil)-2,5-diaza-biciclo[2.2.1]hept-2-il]-4-metil-benzofuran-2-carboxílico ácido 5-[4-(2>4-Dicloro-fenilcarbamoil)-piperidin-1-il]-4-metil-benzofuran-2-carboxílico y las formas estereoisoméricas, mezclas de formas estereoisoméricas o sales farmacéuticamente aceptables de estos.
En algunos aspectos, el agonista de FXR se selecciona del grupo que consiste en los compuestos descritos en el documento WO2008000643, es decir:
hidrógeno cloruro de 2,N-diciclohexil-2-(2-fenil-benzoimidazol-1-il)-acetamida,
ciclohexilamida del ácido 2-[2-(4-cloro-fenil)-benzoimidazol-1 -il]-4-metil-pentanoico,
hidrocloruro del éster metílico del ácido 4-{1-[ciclohexil-(4-morfolin-4-il-fenilcarbamoil)-metil]-1H-benzoimidazol-2-il}-benzoico,
2,N-diciclohexil-2-[5,6-dicloro-2-(2,4-dimetoxi-fenil)-benzoimidazol-1-il]-acetamida,
hidrógeno cloruro de 2-ciclohexil-2-[2-(2,4-dimetoxi-fenil)-benzoimidazol-1 -il]-N-isopropil-acetamida,
hidrógeno cloruro de 2,N-diciclohexil-2-[2-(4-metoxi-fenil)-benzoimidazol-1-il]-acetamida,
hidrógeno cloruro de 2,N-diciclohexil-2-[2-(3-metoxi-fenil)-benzoimidazol-1-il]-acetamida,
hidrógeno cloruro de 2,N-diciclohexil-2-[2-(2-metoxi-fenil)-benzoimidazol-1-il]-acetamida,
hidrógeno cloruro de 2,N-diciclohexil-2-(2-naftalen-1-il-benzoimidazol-1-il)-acetamida,
hidrógeno cloruro de 2,N-diciclohexil-2-[2-(3-etoxi-fenil)-benzoimidazol-1-il]-acetamida,
N-ciclohexil-2-[2-(2,4-dimetoxi-fenil)-benzoimidazol-1-il]-4-fenil-butiramida,
hidrógeno cloruro de N-ciclohexil-2-[2-(2,4-dimetoxi-fenil)-benzoimidazol-1 -il]-3-metil-butiramida,
hidrógeno cloruro de N-ciclohexil-2-[2-(2,4-dimetoxi-fenil)-benzoimidazol-1 -il]-3-fenil-propionamida,
hidrógeno cloruro de N-ciclohexil-2-[2-(2,4-dimetoxi-fenil)-benzoimidazol-1 -il]-2-piridin-2-il-acetamida, hidrógeno cloruro de N-ciclohexil-2-ciclopentil-2-[2-(2,4-dimetoxi-fenil)-benzoimidazol-1 -il]-acetamida, éster metílico del ácido 4-{1 -[ciclohexil-(ciclohexilcarbamoil-metil)]-1 H-benzoimidazol-2-il}-benzoico, 2,N-diciclohexil-2-(2-naftalen-2-il-benzoimidazol-1-il)-acetamida,
2,N-diciclohexil-2-[2-(3-tiofen-2-il-fenil)-benzoimidazol-1-il]-acetamida,
2,N-diciclohexil-2-[2-(5-fenil-tiofen-2-il)-benzoimidazol-1-il]-acetamida,
éster metílico del ácido 3-{1-[ciclohexil-(ciclohexilcarbamoil-metil)]-1H-benzoimidazol-2-il}-benzoico, ciclohexilamida del ácido 2-[2-(3-hidroxi-fenil)-benzoimidazol-1 -il]-4-metil-pentanoico, ciclohexilamida del ácido 2-[2-(4-hidroximetil-fenil)-benzoimidazol-1 -il]-4-metil-pentanoico, ciclohexilamida del ácido 2-[2-(1 H-indol-5-il)-benzoimidazol-1 -il]-4-metil-pentanoico, ciclohexilamida del ácido 2-[2-(1 H-indol-6-il)-benzoimidazol-1 -il]-4-metil-pentanoico, ciclohexilamida del ácido 2-[2-(4-amino-fenil)-benzoimidazol-1 -il]-4-metil-pentanoico,
2-ciclohexil-2-[2-(2,4-dimetoxi-fenil)-benzoimidazol-1-il]-N-((R)1-fenil-etil)-acetamida,
2,N-diciclohexil-2-[2-(4-hidroximetil-fenil)-benzoimidazol-1-il]-acetamida,
N-ciclohexil-2-[2-(2,3-dimetoxi-fenil)-benzoimidazol-1-il]-4-fenil-butiramida,
2-[2-(3-ciano-fenil)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
hidrógeno cloruro de 2,N-diciclohexil-2-{2-[4-(1 H-tetrazol-5-il)-fenil]-benzoimidazol-1 -il}-acetamida, éster metílico del ácido 3-[1 -(bencilcarbamoil-ciclopentil-metil)-1 H-benzoimidazol-2-il]-benzoico, ciclohexilamida del ácido 2-[2-(2,4-dimetoxi-fenil)-benzoimidazol-1 -il]-hexanoico,
hidrógeno cloruro de 2,N-diciclohexil-2-[2-(3-metanosulfonil-fenil)-benzoimidazol-1 -il]-acetamida, N-bencil-2-ciclohexil-2-[2-(2,4-dimetoxi-fenil)-benzoimidazol-1-il]-acetamida,
2-ciclohexil-2-[2-(2,4-dimetoxi-fenil)-benzoimidazol-1-il]-N-(1-metil-butil)-acetamida,
éster metílico del ácido 4-[1 -(bencilcarbamoil-ciclopentil-metil)-1 H-benzoimidazol-2-il]-benzoico, hidrógeno cloruro de N-ciclopentil-2-[2-(3-metoxi-fenil)-benzoimidazol-1 -il]-4-fenil-butiramida, hidrógeno cloruro de 2,N-diciclohexil-2-[2-(2,4-dimetoxi-fenil)-5-metil-benzoimidazol-1 -il]-acetamida, hidrógeno cloruro de 2-[2-(4-cloro-fenil)-benzoimidazol-1-il]-2,N-diciclopentil-acetamida,
N-bencidril-2-ciclohexil-2-[2-(2,4-dimetoxi-fenil)-benzoimidazol-1-il]-acetamida,
N-bencil-2-(2-naftalen-1-il-benzoimidazol-1-il)-4-fenil-butiramida,
2-ciclohexil-2-[2-(2,4-dimetoxi-fenil)-benzoimidazol-1-il]-N-(4-metoxi-fenil)-acetamida,
2,N-diciclohexil-2-[2-(2,4-dimetoxi-fenil)-4-metil-benzoimidazol-1-il]-acetamida,
hidrógeno cloruro de 2,N-diciclohexil-2-{2-[3-(2-oxo-pirrolidin-1 -il)-fenil]-benzoimidazol-1 -il}-acetamida, 2,N-diciclohexil-2-[2-(2-oxo-1,2-dihidro-piridin-4-il)-benzoimidazol-1-il]-acetamida,
N-ciclopentil-2-[2-(2-metoxi-fenil)-benzoimidazol-1-il]-4-fenil-butiramida,
2-ciclohexil-2-[2-(2,4-dimetoxi-fenil)-benzoimidazol-1-il]-N-pentil-acetamida,
hidrógeno cloruro de N-bencil-2-[2-(4-cloro-fenil)-benzoimidazol-1 -il]-2-ciclopentil-acetamida, 2,N-diciclopentil-2-(2-naftalen-1-il-benzoimidazol-1-il)-acetamida,
2-[2-(3-ciano-fenil)-benzoimidazol-1-il]-N-ciclohexil-4-fenil-butiramida,
hidrógeno cloruro de ciclohexilamida del ácido 2-[2-(4-hidroxi-fenil)-benzoimidazol-1-il]-4-metil-pentanoico, N-terc-butil-2-ciclohexil-2-[2-(2,4-dimetoxi-fenil)-benzoimidazol-1-il]-acetamida,
éster metílico del ácido 4-[1 -(1 -bencilcarbamoil-3-fenil-propil)-1 H-benzoimidazol-2-il]-benzoico, éster metílico del ácido 4-[1 -(1 -ciclohexilcarbamoil-3-fenil-propil)-1 H-benzoimidazol-2-il]-benzoico, 2,N-diciclopentil-2-[2-(2-metoxi-fenil)-benzoimidazol-1-il]-acetamida,
2,N-diciclohexil-2-[2-(2,4-dimetoxi-fenil)-nafto[2,3-d]imidazol-1-il]-acetamida,
ciclohexilamida del ácido 2-[2-(2,3-dimetoxi-fenil)-benzoimidazol-1 -il]-4-metil-pentanoico,
N-bencil-2-[2-(2-metoxi-fenil)-benzoimidazol-1-il]-4-fenil-butiramida,
2-ciclohexil-2-[2-(2,4-dimetoxi-fenil)-benzoimidazol-1-il]-N-(3-isopropoxi-propil)-acetamida,
2-[2-(2,4-dimetoxi-fenil)-benzoimidazol-1-il]-N-isopropil-4-fenil-butiramida,
N-bencil-2-ciclopentil-2-(2-naftalen-1-il-benzoimidazol-1-il)-acetamida,
2,N-diciclohexil-2-[2-(2,3-dimetoxi-fenil)-benzoimidazol-1-il]-acetamida,
ciclohexilamida del ácido 2-[2-(2,4-dimetoxi-fenil)-benzoimidazol-1 -il]-4-metil-pentanoico,
2-ciclohexil-2-[2-(2,3-dimetoxi-fenil)-benzoimidazol-1-il]-N-isopropil-acetamida,
2-[2-(2,3-dimetoxi-fenil)-benzoimidazol-1-il]-N-isopropil-4-fenil-butiramida,
2-[2-(4-acetil-fenil)-benzoimidazol-1-il]-N-ciclohexil-4-fenil-butiramida,
hidrógeno cloruro de N-bencil-2-[2-(4-cloro-fenil)-benzoimidazol-1-il]-4-fenil-butiramida,
éster metílico del ácido 4-[1-(1-isopropilcarbamoil-pentil)-1H-benzoimidazol-2-il]-benzoico,
N-butil-2-[2-(2,4-dimetoxi-fenil)-benzoimidazol-1-il]-2-fenil-acetamida,
isopropilamida del ácido 2-[2-(2,3-dimetoxi-fenil)-benzoimidazol-1 -il]-4-metil-pentanoico,
2-benzo[1,3]dioxol-5-il-N-butil-2-[2-(2,3-dimetoxi-fenil)-benzoimidazol-1-il]-acetamida,
2-benzo[1,3]dioxol-5-il-N-butil-2-[2-(2,4-dimetoxi-fenil)-benzoimidazol-1-il]-acetamida,
N-butil-2-[2-(2,4-dimetoxi-fenil)-benzoimidazol-1-il]-2-(2-fluoro-fenil)-acetamida,
N-ciclopentil-2-[2-(3-hidroxi-fenil)-benzoimidazol-1-il]-4-fenil-butiramida,
isopropilamida del ácido 2-[2-(4-acetil-fenil)-benzoimidazol-1-il]-hexanoico,
N-butil-2-[2-(2,3-dimetoxi-fenil)-benzoimidazol-1-il]-2-fenil-acetamida,
ciclohexilamida del ácido 2-[2-(4-acetil-fenil)-benzoimidazol-1 -il]-4-metil-pentanoico,
N-butil-2-[2-(2,3-dimetoxi-fenil)-benzoimidazol-1-il]-2-o-tolil-acetamida,
N-butil-2-[2-(2,3-dimetoxi-fenil)-benzoimidazol-1-il]-2-(4-metoxi-fenil)-acetamida,
N-butil-2-[2-(2,3-dimetoxi-fenil)-benzoimidazol-1-il]-2-(2-fluoro-fenil)-acetamida,
N-butil-2-[2-(2,3-dimetoxi-fenil)-benzoimidazol-1-il]-2-(4-dimetilamino-fenil)-acetamida, isopropilamida del ácido 2-[2-(2,3-dimetoxi-fenil)-benzoimidazol-1 -il]-hexanoico,
éster metílico del ácido 4-{1-[(2-fluoro-fenil)-isopropilcarbamoil-metil]-1H-benzoimidazol-2-il}-benzoico, ciclohexilamida del ácido 2-[2-(3-ciano-fenil)-benzoimidazol-1 -il]-4-metil-pentanoico,
ciclohexilamida del ácido 2-[2-(3-cloro-fenil)-benzoimidazol-1 -il]-4-metil-pentanoico,
N-butil-2-[2-(2,4-dimetoxi-fenil)-benzoimidazol-1-il]-2-(4-metoxi-fenil)-acetamida,
hidrógeno cloruro de N-bencil-2-[2-(3-metoxi-fenil)-benzoimidazol-1-il]-4-fenil-butiramida,
2-(4-cloro-fenil)-2-[2-(2,3-dimetoxi-fenil)-benzoimidazol-1-il]-N-isopropil-acetamida,
N-butil-2-[2-(2,4-dimetoxi-fenil)-benzoimidazol-1-il]-2-(4-dimetilamino-fenil)-acetamida,
2-[2-(4-hidroxi-fenil)-benzoimidazol-1-il]-N-isopropil-4-fenil-butiramida,
ciclohexilamida del ácido 2-[2-(4-hidroxi-fenil)-benzoimidazol-1 -il]-4-metil-pentanoico,
2-[2-(3-cloro-fenil)-benzoimidazol-1-il]-N-isopropil-4-fenil-butiramida,
N-butil-2-(4-cloro-fenil)-2-[2-(2,4-dimetoxi-fenil)-benzoimidazol-1-il]-acetamida,
2-[2-(3-ciano-fenil)-benzoimidazol-1-il]-N-isopropil-4-fenil-butiramida,
2-[2-(4-acetil-fenil)-benzoimidazol-1-il]-N-isopropil-2-(4-metoxi-fenil)-acetamida,
éster metílico del ácido 4-{1-[isopropilcarbaniol-(4-metoxi-fenil)-metil]-1H-benzoimidazol-2-il}-benzoico,
éster metílico del ácido 4-[1-(isopropilcarbamoil-fenil-metil-1H-benzoimidazol-2-il]-benzoico,
N-isopropil-2-[2-(1 -metil-1 H-pirrol-2-il)-benzoimidazol-1 -il]-4-fenil-butiramida,
isopropilamida del ácido 2-[2-(3-ciano-fenil)-benzoimidazol-1 -il]-hexanoico,
isopropilamida del ácido 2-[2-(4-hidroxi-fenil)-benzoimidazol-1 -il]-pentanoico,
2-benzo-[1,3]dioxol-5-il-N-butil-2-[2-(1 -metil-1 H-pirrol-2-il)-benzoimidazol-1 -il]-acetamida,
2-ciclohexil-2-[2-(2,4-dimetoxi-fenil)-benzoimidazol-1-il]-N-(2,6-dimetil-fenil)-acetamida,
2,N-diciclohexil-2-[2-(2,4-dimetoxi-fenil)-benzoimidazol-1-il]-acetamida,
2-ciclohex-3-enil-N-ciclohexil-2-[2-(2,4-dimetoxi-fenil)-benzoimidazol-1-il]-acetamida,
hidrógeno cloruro de 2-[2-(4-ciano-fenil)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
2-ciclohexil-N-ciclopentil-2-[2-(2,4-dimetoxi-fenil)-benzoimidazol-1-il]-acetamida,
2,N-diciclohexil-2-[2-(2,4-dimetoxi-fenil)-5,6-difluoro-benzoimidazol-1-il]-acetamida,
2,N-diciclohexil-2-[2-(2,4-dimetoxi-fenil)-6-metil-benzoimidazol-1-il]-acetamida,
2-[2-(4-cloro-fenil)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
hidrógeno cloruro de 2,N-diciclohexil-2-[2-(4-sulfamoil-fenil)-benzoimidazol-1-il]-acetamida,
2-ciclohexil-2-[2-(2,4-dimetoxi-fenil)-benzoimidazol-1-il]-N-(1,1,3,3-tetrametil-butil)-acetamida,
hidrógeno cloruro del éster metílico del ácido 4-{[1-ciclopentil-(ciclopentilcarbamoil-metil)]-1H-benzoimidazol-2-il}-benzoico,
hidrógeno cloruro de 2,N-diciclohexil-2-(2-quinolin-6-il-benzoimidazol-1-il)-acetamida,
2-[2-(4-amino-fenil)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
hidrógeno cloruro de ciclohexilamida del ácido 2-[2-(2,4-dimetoxi-fenil)-benzoimidazol-1 -il]-5-fenil-pentanoico, éster metílico del ácido 4-[1-(1-ciclopentilcarbamoil-3-fenil-propil)-1H-benzoimidazol-2-il]-benzoico,
hidrógeno cloruro de 2,N-diciclohexil-2-[2-(4-dimetilsulfamoil-fenil)-benzoimidazol-1 -il]-acetamida,
hidrógeno cloruro de 2,N-diciclohexil-2-[2-(3-sulfamoil-fenil)-benzoimidazol-1-il]-acetamida,
hidrógeno cloruro de 2,N-diciclohexil-2-{2-[3-(1 H-tetrazol-5-il)-fenil]-benzoimidazol-1 -il}-acetamida,
hidrógeno cloruro de 2,N-diciclohexil-2-{2-[4-(1 H-imidazol-2-il)-fenil]-benzoimidazol-1 -il}-acetamida,
hidrógeno cloruro de 2,N-diciclohexil-2-[2-(4-imidazol-1 -il-fenil)-benzoimidazol-1 -il]-acetamida,
hidrógeno cloruro de 2,N-diciclohexil-2-[2-(4-[1,2,4]triazol-4-il-fenil)-benzoimidazol-1 -il]-acetamida,
hidrógeno cloruro de 2,N-diciclohexil-2-{2-[4-(1 H-pirazol-4-il)-fenil]-benzoimidazol-1 -il}-acetamida,
hidrógeno cloruro de 2,N-diciclohexil-2-[2-(4-[1,2,3]tiadiazol-4-il-fenil)-benzoimidazol-1 -il]-acetamida, hidrógeno cloruro de 2,N-diciclohexil-2-[2-(1,3-dioxo-2,3-dihidro-1 H-isoindol-5-il)-benzoimidazol-1 -il]-acetamida, hidrógeno cloruro de 2,N-diciclohexil-2-[2-(3-tetrazol-1 -il-fenil)-benzoimidazol-1 -il]-acetamida,
hidrógeno cloruro del éster metílico del ácido 4-[1-(ciclohexil-3-metoxicarbonilfenilcarbamoil-metil)-1H-benzoimidazol-2-il]-benzoico,
hidrógeno cloruro del éster metílico del ácido trans 4-(1 -{ciclohexil-[(4-metoxicarbonil-ciclohexilmetil)-carbamoil]-metil}-1 H-benzoimidazol-2-il)-benzoico,
hidrógeno cloruro del éster etílico del ácido 4-{2-ciclohexil-2-[2-(4-metoxicarbonil-fenil)-benzoimidazol-1-il]-acetilamino}-piperidin-1-carboxílico,
hidrógeno cloruro de N-ciclohexil-2-[2-(2,4-dimetoxi-fenil)-benzoimidazol-1 -il]-2-fenil-acetamida,
hidrógeno cloruro del éster metílico del ácido 4-(1-{ciclohexil-[3-(2-oxo-pirrolidin-1-il)-propilcarbamoil]-metil}-1H-benzoimidazol-2-il)-benzoico,
hidrógeno cloruro del éster metílico del ácido 4-{1-[ciclohexil-(3-metoxicarbonil-propilcarbamoil)-metil]-1H-benzoimidazol-2-il}-benzoico,
hidrógeno cloruro del éster metílico del ácido 4-{1-[ciclohexil-(4-metoxicarbonil-butilcarbamoil)-metil]-1H-benzoimidazol-2-il}-benzoico,
hidrógeno cloruro del éster metílico del ácido 4-{1-[ciclohexil-(5-metoxicarbonil-pentilcarbamoil)-metil]-1H-benzoimidazol-2-il}-benzoico,
hidrógeno cloruro de 2-ciclohexil-2-[2-(2,4-dimetoxi-fenil)-benzoimidazol-1 -il]-N-metil-acetamida,
2-[2-(4-Acetilamino-fenil)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
2-[2-(3-acetilamino-fenil)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
hidrógeno cloruro del éster metílico del ácido 4-{1-[ciclohexil-(3-formilamino-fenilcarbamoil)-metil]-1H-benzoimidazol-2-il}-benzoico,
N-ciclopentil-2-(2-naftalen-1-il-benzoimidazol-1-il)-propionamida,
2,N-Diciclohexil-2-(2-fenil-benzoimidazol-1-il)-acetamida,
2-[1-(Ciclohexil-ciclohexilcarbaniol-metil)-1 H-benzoimidazol-2-il]-benzamida,
2-[2-(5-Amino-piridin-2-il)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
2,N-Diciclohexil-2-[2-(2-etil-5-metil-2H-pirazol-3-il)-benzoimidazol-1-il]-acetamida,
2,N-Diciclohexil-2-[2-(5-metil-isoxazol-4-il)-benzoimidazol-1-il]-acetamida,
2,N-Diciclohexil-2-[2-(1 H-pirrol-2-il)-benzoimidazol-1-il]-acetamida,
2,N-Diciclohexil-2-(2-furan-2-il-benzoimidazol-1-il)-acetamida,
2-[6-bromo-2-(4-cloro-fenil)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
2-[6-Cloro-2-(4-cloro-fenil)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
2-[2-(4-Cloro-fenil)-6-metoxi-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
[6-Cloro-2-(4-cloro-fenil)-5-fluoro-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
(S)-2,N-Diciclohexil-2-[2-(2,4-dimetoxi-fenil)-benzoimidazol-1-il]-acetamida,
(S)-2-[2-(4-Cloro-fenil)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
2-[1-(Ciclohexil-ciclohexilcarbamoil-metil)-1 H-benzoimidazol-2-il]-N-metil-benzamida,
2,N-Diciclohexil-2-(2-furan-3-il-benzoimidazol-1-il)-acetamida,
2,N-Diciclohexil-2-[2-(3-metil-furan-2-il)-benzoimidazol-1-il]-acetamida,
,N-Diciclohexil-2-[2-(3-metil-isoxazol-5-il)-benzoimidazol-1-il]-acetamida, ,N-Diciclohexil-2-(2-m-tolil-benzoimidazol-1-il)-acetamida,
,N-Diciclohexil-2-[2-(3-fluoro-fenil)-benzoimidazol-1-il]-acetamida,
,N-Diciclohexil-2-[2-(2-fluoro-fenil)-benzoimidazol-1-il]-acetamida,
,N-Diciclohexil-2-[2-(3,5-dimetil-isoxazol-4-il)-benzoimidazol-1-il]-acetamida, ,N-Diciclohexil-2-[2-(3-metil-tiofen-2-il)-benzoimidazol-1-il]-acetamida,
,N-Diciclohexil-2-[2-(4-vinil-fenil)-benzoimidazol-1-il]-acetamida,
,N-Diciclohexil-2-[2-(2,3-dimetil-fenil)-benzoimidazol-1-il]-acetamida,
,N-Diciclohexil-2-[2-(3,4-dimetil-fenil)-benzoimidazol-1-il]-acetamida,
,N-Diciclohexil-2-[2-(4-etil-fenil)-benzoimidazol-1-il]-acetamida,
,N-Diciclohexil-2-[2-(2,4-dimetil-fenil)-benzoimidazol-1-il]-acetamida,
,N-Diciclohexil-2-[2-(2-etil-fenil)-benzoimidazol-1-il]-acetamida,
,N-Diciclohexil-2-[2-(4-fluoro-3-metil-fenil)-benzoimidazol-1-il]-acetamida, ,N-Diciclohexil-2-[2-(3-fluoro-4-metil-fenil)-benzoimidazol-1-il]-acetamida, ,N-Diciclohexil-2-[2-(2,6-difluoro-fenil)-benzoimidazol-1-il]-acetamida,
,N-Diciclohexil-2-[2-(3,5-difluoro-fenil)-benzoimidazol-1-il]-acetamida,
,N-Diciclohexil-2-[2-(2,5-difluoro-fenil)-benzoimidazol-1-il]-acetamida,
,N-Diciclohexil-2-[2-(3,4-difluoro-fenil)-benzoimidazol-1-il]-acetamida,
,N-Diciclohexil-2-[2-(2,3-difluoro-fenil)-benzoimidazol-1-il]-acetamida,
,N-Diciclohexil-2-[2-(1 H-indol-4-il)-benzoimidazol-1-il]-acetamida,
,N-Diciclohexil-2-[2-(1 H-indol-6-il)-benzoimidazol-1-il]-acetamida,
-[2-(5-Cloro-tiofen-2-il)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
-[2-(4-Acetil-fenil)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
-[2-(2-Acetil-fenil)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
,N-Diciclohexil-2-[2-(4-isopropil-fenil)-benzoimidazol-1-il]-acetamida,
-[2-(4-Ciano-2-fluoro-fenil)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida, ,N-Diciclohexil-2-[2-(2-dimetilamino-fenil)-benzoimidazol-1-il]-acetamida, ,N-Diciclohexil-2-[2-(3-dimetilamino-fenil)-benzoimidazol-1-il]-acetamida, ,N-Diciclohexil-2-[2-(4-metoxi-3-metil-fenil)-benzoimidazol-1-il]-acetamida, ,N-Diciclohexil-2-[2-(4-metoxi-2-metil-fenil)-benzoimidazol-1-il]-acetamida, ,N-Diciclohexil-2-[2-(3-metoxi-4-metil-fenil)-benzoimidazol-1-il]-acetamida, ,N-Diciclohexil-2-[2-(2-etoxi-fenil)-benzoimidazol-1-il]-acetamida,
-[2-(6-Cloro-piridin-3-il)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida, -[2-(2-Cloro-piridin-4-il)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida, -[2-(4-Cloro-fenil)-6-fluoro-benzoimidazol-1-il]-2,N-diciclohexil-acetamida, ,N-Diciclohexil-2-[2-(3-fluoro-4-metoxi-fenil)-benzoimidazol-1-il]-acetamida, -[2-(4-Cloro-3-metil-fenil)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
2-[2-(3-Cloro-2-metil-fenil)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida, 2-[2-(4-Cloro-3-fluoro-fenil)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida, 2-[2-(3-Cloro-4-fluoro-fenil)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida, 2,N-Diciclohexil-2-[2-(5-metil-1 H-indol-2-il)-benzoimidazol-1-il]-acetamida, 2,N-Diciclohexil-2-[2-(2,3,4-trifluoro-fenil)-benzoimidazol-1-il]-acetamida, 2,N-Diciclohexil-2-[2-(2,4,5-trifluoro-fenil)-benzoimidazol-1-il]-acetamida, 2-(2-Benzo[b]tiofen-2-il-benzoimidazol-1-il)-2,N-diciclohexil-acetamida,
2,N-Diciclohexil-2-[2-(5-fluoro-1 H-indol-2-il)-benzoimidazol-1-il]-acetamida, 2-(2-Benzotiazol-6-il-benzoimidazol-1-il)-2,N-diciclohexil-acetamida,
2,N-Diciclohexil-2-[2-(4-isopropoxi-fenil)-benzoimidazol-1-il]-acetamida, 2,N-Diciclohexil-2-[2-(3,4-dimetoxi-fenil)-benzoimidazol-1-il]-acetamida, 2,N-Diciclohexil-2-[2-(2,5-dimetoxi-fenil)-benzoimidazol-1-il]-acetamida, 2,N-Diciclohexil-2-[2-(2-difluorometoxi-fenil)-benzoimidazol-1-il]-acetamida, 2,N-Diciclohexil-2-[2-(4-difluorometoxi-fenil)-benzoimidazol-1-il]-acetamida, 2,N-Diciclohexil-2-[2-(3-difluorometoxi-fenil)-benzoimidazol-1-il]-acetamida, 2,N-Diciclohexil-2-[2-(4-trifluorometil-fenil)-benzoimidazol-1-il]-acetamida, 2,N-Diciclohexil-2-[2-(3,4-dicloro-fenil)-benzoimidazol-1-il]-acetamida,
2-[2-(4-Bromo-fenil)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
2,N-Diciclohexil-2-[2-(6-metoxi-naftalen-2-il)-benzoimidazol-1-il]-acetamida, 2,N-Diciclohexil-2-[2-(3-trifluorometoxi-fenil)-benzoimidazol-1-il]-acetamida, 2,N-Diciclohexil-2-[2-(7-etoxi-benzofuran-2-il)-benzoimidazol-1-il]-acetamida, 2,N-Diciclohexil-2-[2-(3-fluoro-4-trifluorometil-fenil)-benzoimidazol-1-il]-acetamida, 2,N-Diciclohexil-2-[2-(6-dietilamino-piridin-3-il)-benzoimidazol-1-il]-acetamida, 2-[2-(2-Cloro-5-metil-fenil)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida, 2-[2-(5-Cloro-2-metil-fenil)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida, 2-[2-(2-Cloro-6-metil-fenil)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida, 2,N-Diciclohexil-2-(2-quinoxalin-6-il-benzoimidazol-1-il)-acetamida,
2-[2-(5-Cloro-2-fluoro-fenil)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida, 2,N-Diciclohexil-2-[2-(4-metoxi-3,5-dimetil-fenil)-benzoimidazol-1-il]-acetamida, 2,N-Diciclohexil-2-[2-(2,3-dimetoxi-fenil)-benzoimidazol-1-il]-acetamida, 2-[2-(3-Cloro-4-metoxi-fenil)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida, 2,N-Diciclohexil-2-[2-(2,5-dicloro-fenil)-benzoimidazol-1-il]-acetamida,
2-[2-(3-Cloro-2,4-difluoro-fenil)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida, 2-[2-(2-Cloro-4,5-difluoro-fenil)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida, 2,N-Diciclohexil-2-[2-(4-dietilamino-fenil)-benzoimidazol-1-il]-acetamida, 2-[2-(4-Benzoil-fenil)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
(S)-2-[2-(4-Ciano-fenil)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
2,N-Diciclohexil-2-[2-(4-fenoxi-fenil)-benzoimidazol-1-il]-acetamida,
2,N-Diciclohexil-2-[2-(2-fenoxi-fenil)-benzoimidazol-1-il]-acetamida,
2,N-Diciclohexil-2-[2-(3-fenoxi-fenil)-benzoimidazol-1-il]-acetamida,
2,N-Diciclohexil-2-{2-[2-(1,1,2,2-tetrafluoro-etoxi)-fenil]-benzoimidazol-1 -il}-acetamida, 2,N-Diciclohexil-2-{2-[3-(1,1,2,2-tetrafluoro-etoxi)-fenil]-benzoimidazol-1 -il}-acetamida, 2,N-Diciclohexil-2-{2-[4-(1,1,2,2-tetrafluoro-etoxi)-fenil]-benzoimidazol-1 -il}-acetamida, 2,N-Diciclohexil-2-[2-(4’-trifluorometil-bifenil-4-il)-benzoimidazol-1-il]-acetamida,
2,N-Diciclohexil-2-[2-(3’,4’-dicloro-bifenil-4-il)-benzoimidazol-1-il]-acetamida,
2,N-Diciclohexil-2-[2-(2,4-dicloro-5-sulfamoil-fenil)-benzoimidazol-1-il]-acetamida, (S)-2-[6-Cloro-2-(4-cloro-pentil)-5-fluoro-benzoimidazol-1-il]-2,N-diciclohexil-acetamida, 2,N-Diciclohexil-2-(2-piridin-2-il-benzoimidazol-1-il)-acetamida,
2,N-Diciclohexil-2-[2-(6-metil-piridin-3-il)-benzoimidazol-1-il]-acetamida,
2,N-Diciclohexil-2-[2-(3-metil-piridin-2-il)-benzoimidazol-1-il]-acetamida,
2,N-Diciclohexil-2-[2-(6-metil-piridin-2-il)-benzoimidazol-1-il]-acetamida,
2-[2-(2-Amino-piridin-3-il)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
2-[2-(6-Ciano-piridin-3-il)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
2,N-Diciclohexil-2-[2-(2-metoxi-piridin-3-il)-benzoimidazol-1-il]-acetamida,
2-[2-(2-Cloro-6-metil-piridin-3-il)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
2-[2-(2-Cloro-6-metil-piridin-4-il)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
2,N-Diciclohexil-2-(2-quinolin-3-il-benzoimidazol-1-il)-acetamida,
2,N-Diciclohexil-2-(2-quinolin-4-il-benzoimidazol-1-il)-acetamida,
2-[2-(3-Cloro-4-trifluorometil-fenil)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida, ciclohexilamida del ácido (S)-2-[2-(4-Cloro-fenil)-benzoimidazol-1 -il]-4-metil-pentanoico, 2-(4-Cloro-fenil)-2-[2-(4-cloro-fenil)-benzoimidazol-1-il]-N-ciclohexil-acetamida,
2-[2-(4-Cloro-fenil)-benzoimidazol-1-il]-N-ciclohexil-2-(4-trifluorometil-fenil)-acetamida, 2-[2-(4-Cloro-fenil)-benzoimidazol-1-il]-N-ciclohexil-2-(3,4-dicloro-fenil)-acetamida, 2-[2-(4-Cloro-fenil)-benzoimidazol-1-il]-N-ciclohexil-2-(3-metoxi-fenil)-acetamida,
2-[2-(4-Cloro-fenil)-benzoimidazol-1-il]-N-ciclohexil-2-p-tolil-acetamida,
2-[2-(4-Cloro-fenil)-benzoimidazol-1-il]-N-ciclohexil-2-(3-fluoro-fenil)-acetamida,
2-[2-(4-Cloro-fenil)-benzoimidazol-1-il]-N-ciclohexil-2-(4-difluorometoxi-fenil)-acetamida, 2-[2-(4-Cloro-fenil)-benzoimidazol-1-il]-N-ciclohexil-2-(2,5-difluoro-fenil)-acetamida, 2-[2-(4-Cloro-fenil)-benzoimidazol-1-il]-N-ciclohexil-2-(2-fluoro-5-metoxi-fenil)-acetamida, (S)-2-[2-(5-Cloro-2-fluoro-fenil)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
(S)-2,N-Diciclohexil-2-[2-(2,3-dimetoxi-fenil)-benzoimidazol-1-il]-acetamida,
(S)-2-[2-(3-Cloro-4-metoxi-fenil)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
(S)-2-Ciclohexil-2-[2-(2,4-dimetoxi-fenil)-benzoimidazol-1-il]-N-(2,6-dimetil-fenil)-acetamida, 2-[2-(4-Cloro-fenil)-benzoimidazol-1-il]-2-ciclohexil-N-(4,4-difluoro-ciclohexil)-acetamida,
(S)-2-[2-(4-Cloro-fenil)-benzoimidazol-1-il]-2-ciclohexil-N-(4,4-difluoro-ciclohexil)-acetamida, (S)-2-[2-(2-Amino-piridin-3-il)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
2,N-Diciclohexil-2-(6-fluoro-2-piridin-2-il-benzoimidazol-1-il)-acetamida,
2,N-Diciclohexil-2-[2-(2,4-dimetoxi-fenil)-6-fluoro-benzoimidazol-1-il]-acetamida,
2,N-Diciclohexil-2-[6-fluoro-2-(4-metoxi-fenil)-benzoimidazol-1-il]-acetamida,
2,N-Diciclohexil-2-[2-(2,3-difluoro-fenil)-6-fluoro-benzoimidazol-1-il]-acetamida,
2,N-Diciclohexil-2-[2-(2,3-dimetoxi-fenil)-6-fluoro-benzoimidazol-1-il]-acetamida,
2,N-Diciclohexil-2-[2-(2-etil-5-metil-2H-pirazol-3-il)-6-fluoro-benzoimidazol-1-il]-acetamida,
2,N-Diciclohexil-2-[2-(3,5-dimetil-isoxazol-4-il)-6-fluoro-benzoimidazol-1-il]-acetamida,
2,N-Diciclohexil-2-[6-fluoro-2-(1 H-pirazol-4-il)-benzoimidazol-1-il]-acetamida,
2,N-Diciclohexil-2-[2-(1,5-dimetil-1 H-pirazol-3-il)-6-fluoro-benzoimidazol-1 -il]-acetamida,
2,N-Diciclohexil-2-[6-fluoro-2-(3-metil-isoxazol-5-il)-benzoimidazol-1-il]-acetamida,
2,N-Diciclohexil-2-[6-fluoro-2-(1 H-pirrol-2-il)-benzoimidazol-1-il]-acetamida,
2,N-Diciclohexil-2-[6-fluoro-2-(3-metil-tiofen-2-il)-benzoimidazol-1-il]-acetamida,
N-Bencil-2-[2-(4-cloro-fenil)-benzoimidazol-1-il]-2-ciclohexil-acetamida,
N-Butil-2-[2-(4-cloro-fenil)-benzoimidazol-1-il]-2-ciclohexil-acetamida,
2-[2-(4-Cloro-fenil)-benzoimidazol-1-il]-N-ciclohexil-2-(tetrahidro-piran-4-il)-acetamida,
2-[5-cloro-2-(4-Cloro-fenil)-6-fluoro-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
2-[2-(4-Cloro-fenil)-5,6-difluoro-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
2-[2-(4-Cloro-fenil)-benzoimidazol-1-il]-2-ciclohexil-N-(tetrahidro-piran-4-il)-acetamida,
2-[2-(4-Cloro-fenil)-benzoimidazol-1-il]-2-ciclohexil-N-ciclopropil-acetamida,
2,N-Diciclohexil-2-[2-(6-morfolin-4-il-piridin-3-il)-benzoimidazol-1-il]-acetamida,
(S)-2-[2-(4-Cloro-fenil)-benzoimidazol-1-il]-2-ciclohexil-N-(tetrahidro-piran-4-il)-acetamida,
(S)-2,N-Diciclohexil-2-[2-(4-metanosulfonil-fenil)-benzoimidazol-1-il]-acetamida,
(S)-2-[2-(4-Cloro-fenil)-benzoimidazol-1-il]-2-ciclohexil-N-ciclopropil-acetamida,
2-[6-Cloro-2-(4-cloro-fenil)-5-fluoro-benzoimidazol-1-il]-N-ciclohexil-2-(tetrahidro-piran-4-il)-acetamida, (S)-2-[2-(4-Cloro-fenil)-benzoimidazol-1-il]-N-ciclohexil-2-(tetrahidro-piran-4-il)-acetamida,
(S)-2-[6-Cloro-2-(4-cloro-fenil)-5-fluoro-benzoimidazol-1-il]-N-ciclohexil-2-(tetrahidro-piran-4-il)-acetamida, (S)-2-[2-(4-Cloro-fenil)-5,6-difluoro-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
(S)-2-[2-(5-Cloro-tiofen-2-il)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
(S)-2,N-Diciclohexil-2-[2-(2,3-difluoro-fenil)-6-fluoro-benzoimidazol-1-il]-acetamida,
2-[6-Cloro-2-(4-cloro-fenil)-5-fluoro-benzoimidazol-1-il]-N-ciclohexil-2-ciclopentil-acetamida, ciclohexilamida del ácido (S)-2-[6-cloro-2-(4-cloro-fenil)-5-fluoro-benzoimidazol-1 -il]-heptanoico,
(S)-2-[6-Cloro-2-(4-cloro-fenil)-5-fluoro-benzoimidazol-1-il]-N-ciclohexil-2-ciclopentil-acetamida,
2-[2-(4-Cloro-fenil)-5-fluoro-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
éster metílico del ácido 2-[1-(ciclohexil-ciclohexilcarbamoil-metil)-5,6-difluoro-1H-benzoimidazol-2-il]-benzoico, 2,N-Diciclohexil-2-(5,6-difluoro-2-piridin-2-il-benzoimidazol-1-il)-acetamida,
2-[2-(5-Cloro-tiofen-2-il)-5,6-difluoro-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
éster metílico del ácido 2-[6-cloro-1 -(ciclohexil-ciclohexilcarbamoil-metil)-5-fluoro-1 H-benzoimidazol-2-il]-benzoico, 2-(6-Cloro-5-fluoro-2-piridin-2-il-benzoimidazol-1-il)-2,N-diciclohexil-acetamida,
2-(6-Cloro-5-fluoro-2-piridin-3-il-benzoimidazol-1-il)-2,N-diciclohexil-acetamida,
2-(6-Cloro-5-fluoro-2-piridin-4-il-benzoimidazol-1-il)-2,N-diciclohexil-acetamida,
2-[6-Cloro-2-(3-cloro-tiofen-2-il)-5-fluoro-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
2-[6-Cloro-2-(5-cloro-tiofen-2-il)-5-fluoro-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
ciclohexilamida del ácido (S)-2-[6-cloro-2-(4-cloro-fenil)-5-fluoro-benzoimidazol-1 -il]-3-etil-pentanoico,
2-[6-Cloro-5-fluoro-2-(4-fluoro-fenil)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
2-[2-(4-Cloro-fenil)-benzoimidazol-1-il]-2-ciclohexil-N-(1-isopropil-2-metil-propil)-acetamida,
2-[6-Cloro-2-(4-cloro-fenil)-5-fluoro-benzoimidazol-1-il]-2-ciclohexil-N-ciclopentil-acetamida,
2-[2-(4-Cloro-fenil)-5,6-difluoro-benzoimidazol-1-il]-N-ciclohexil-2-(tetrahidro-piran-4-il)-acetamida,
(S)-2-[2-(4-Cloro-fenil)-5-fluoro-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
2-[2-(4-Cloro-fenil)-5,6-difluoro-benzoimidazol-1-il]-2-ciclohexil-N-(tetrahidro-piran-4-il)-acetamida,
2-[6-Cloro-2-(4-cloro-fenil)-5-fluoro-benzoimidazol-1-il]-2-ciclohexil-N-(tetrahidro-piran-4-il)-acetamida,
2,N-Diciclohexil-2-[2-(3-dietilamino-fenil)-5,6-difluoro-benzoimidazol-1-il]-acetamida,
2,N-Diciclohexil-2-[2-(3-dietilamino-fenil)-6-fluoro-benzoimidazol-1-il]-acetamida,
2-[2-(4-Cloro-fenil)-5,6-difluoro-benzoimidazol-1-il]-2-ciclohexil-N-(1-isopropil-2-metil-propil)-acetamida,
2-[6-Cloro-2-(4-cloro-fenil)-5-fluoro-benzoimidazol-1-il]-2-ciclohexil-N-(1-isopropil-2-metil-propil)-acetamida, 2-[2-(3-Cloro-fenil)-5,6-difluoro-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
2-[2-(2-Cloro-fenil)-5,6-difluoro-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
(S)-2-[6-Cloro-5-fluoro-2-(4-fluoro-fenil)-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
(S)-2-[2-(4-Cloro-fenil)-5,6-difluoro-benzoimidazol-1-il]-N-ciclohexil-2-(tetrahidro-piran-4-il)-acetamida,
2-[2-(4-Cloro-fenil)-5-fluoro-benzoimidazol-1-il]-N-ciclohexil-2-(tetrahidro-piran-4-il)-acetamida,
2-[2-(4-Cloro-fenil)-6-fluoro-benzoimidazol-1-il]-N-ciclohexil-2-(tetrahidro-piran-4-il)-acetamida,
2-[2-(4-Cloro-fenil)-6-fluoro-benzoimidazol-1-il]-N-ciclohexil-2-(tetrahidro-piran-2-il)-acetamida,
2-[6-Cloro-2-(4-cloro-fenil)-5-fluoro-benzoimidazol-1-il]-N-ciclohexil-2-(tetrahidro-piran-2-il)-acetamida,
(S)-2,N-Diciclohexil-2-[6-fluoro-2-(3-metil-tiofen-2-il)-benzoimidazol-1-il]-acetamida,
(S)-2-[2-(2-Cloro-fenil)-5,6-difluoro-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
(S)-2-[2-(4-Cloro-fenil)-5-fluoro-benzoimidazol-1-il]-N-ciclohexil-2-(tetrahidro-piran-4-il)-acetamida,
(S)-2-[2-(4-Cloro-fenil)-6-fluoro-benzoimidazol-1-il]-N-ciclohexil-2-(tetrahidro-piran-4-il)-acetamida,
(S)-2-[2-(4-Cloro-fenil)-6-fluoro-benzoimidazol-1-il]-N-ciclohexil-2-(R)-tetrahidro-piran-2-il-acetamida,
(S)-2-[2-(4-Cloro-fenil)-6-fluoro-benzoimidazol-1-il]-N-ciclohexil-2-(S)-tetrahidro-piran-2-il-acetamida,
2-[2-(4-Cloro-fenil)-5-fluoro-benzoimidazol-1-il]-N-ciclohexil-2-(tetrahidro-piran-2-il)-acetamida,
2,N-Diciclohexil-2-[2-(3,4-dicloro-fenil)-6-metoxi-benzoimidazol-1-il]-acetamida,
2-[2-(4-Cloro-fenil)-6-metoxi-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
2-[2-(5-Cloro-tiofen-2-il)-6-metoxi-benzoimidazol-1 -il]-2,N-diciclohexil-acetamida,
2-[2-(3-Cloro-4-metoxi-fenil)-6-metoxi-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
2-[2-(4-Cloro-3-fluoro-fenil)-6-metoxi-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
2-Ciclohexil-N-ciclopentil-2-[2-(3,4-dicloro-fenil)-6-metoxi-benzoimidazol-1-il]-acetamida,
2-[2-(4-Cloro-fenil)-6-metoxi-benzoimidazol-1-il]-2-ciclohexil-N-ciclopentil-acetamida,
2-[2-(3-Cloro-fenil)-6-metoxi-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
2,N-Diciclopentil-2-[2-(3,4-dicloro-fenil)-6-metoxi-benzoimidazol-1-il]-acetamida,
2-[2-(4-Cloro-fenil)-6-metoxi-benzoimidazol-1-il]-N-ciclohexil-2-ciclopentil-acetamida,
2-[2-(4-Cloro-3-fluoro-fenil)-6-metoxi-benzoimidazol-1-il]-2-ciclohexil-N-ciclopentil-acetamida,
2-[2-(3-Cloro-4-metoxi-fenil)-6-metoxi-benzoimidazol-1-il]-2-ciclohexil-N-ciclopentil-acetamida,
2,N-Diciclohexil-2-[2-(4-fluoro-fenil)-6-metoxi-benzoimidazol-1-il]-acetamida,
2-[2-(3-Cloro-fenil)-6-metoxi-benzoimidazol-1-il]-2-ciclohexil-N-ciclopentil-acetamida,
2-[2-(3-Cloro-4-metoxi-fenil)-6-metoxi-benzoimidazol-1-il]-N-ciclohexil-2-ciclopentil-acetamida,
2-[2-(5-Cloro-tiofen-2-il)-6-metoxi-benzoimidazol-1 -il]-N-ciclohexil-2-ciclopentil-acetamida,
2-Ciclobutil-N-ciclohexil-2-[2-(3,4-dicloro-fenil)-6-metoxi-benzoimidazol-1-il]-acetamida,
2-[2-(5-Cloro-tiofen-2-il)-6-metoxi-benzoimidazol-1 -il]-2-ciclohexil-N-ciclopentil-acetamida,
2-[2-(6-Cloro-piridin-3-il)-6-metoxi-benzoimidazol-1-il]-2,N-diciclohexil-acetamida,
2-[2-(3-Cloro-fenil)-6-metoxi-benzoimidazol-1-il]-N-ciclohexil-2-ciclopentil-acetamida,
2-[2-(3-Cloro-4-metoxi-fenil)-6-metoxi-benzoimidazol-1-il]-2,N-diciclopentil-acetamida,
2,N-Diciclohexil-2-[6-metoxi-2-(6-trifluorometil-piridin-3-il)-benzoimidazol-1-il]-acetamida,
2-[2-(5-Cloro-tiofen-2-il)-6-metoxi-benzoimidazol-1 -il]-2-ciclobutil-N-ciclohexil-acetamida,
2-[2-(3-Cloro-fenil)-6-metoxi-benzoimidazol-1-il]-2-ciclobutil-N-ciclohexil-acetamida, y
N-Ciclohexil-2-ciclopentil-2-[2-(4-fluoro-fenil)-6-metoxi-benzoimidazol-1-il]-acetamida,
y sales y ésteres farmacéuticamente aceptables de estos.
En algunos aspectos, el agonista de FXR se selecciona del grupo que consiste en los compuestos descritos en el documento US2009215748, es decir:
éster etílico del ácido (3,4-difluoro-benzoil)-4,4-dimetil-5,6-dihidro-4H-tieno[2,3-d]azepin-8-carboxílico,
éster etílico del ácido 3-(3,4-difluoro-benzoil)-1,1,6-trimetil-1,2,3,6-tetrahidro-azepin[4,5-b]indol-5-carboxílico, éster etílico del ácido 3-(3,4-difluoro-benzoil)-1,1-dimetilen-1,2,3,6-tetrahidro-azepin[4,5-b]indol-5-carboxílico, éster isopropílico del ácido 3-(3,4-difluoro-benzoil)-1,1-dimetilen-1,2,3,6-tetrahidro-azepin[4,5-b]indol-5-carboxílico, éster etílico del ácido 3-(3,4-difluoro-benzoil)-1,1-tetrametilen-1,2,3,6-tetrahidro-azepin[4,5-b]indol-5-carboxílico, éster etílico del ácido 3-(3,4-difluoro-benzoil)-1, 1 -trimetilen-1,2,3,6-tetrahidro-azepin[4,5-b]indol-5-carboxílico, ciclobutilamida del ácido 3-(3,4-difluoro-benzoil)-1 -metil-1,2,3,6-tetrahidro-azepin[4,5-b]indol-5-carboxílico, ciclobutilamida del ácido 3-(3,4-difluoro-benzoil)-2-metil-1,2,3,6-tetrahidro-azepin[4,5-b]indol-5-carboxílico, éster etílico del ácido 3-(3-fluoro-benzoil)-1,2,3,6-tetrahidro-azepin[4,5-b]indol-5-carboxílico,
éster etílico del ácido 3-(4-fluoro-benzoil)-1, 1 -dimetil-1,2,3,4,5,6,7,8,9,10-decahidro-azepin[4,5-b]indol-5-carboxílico, éster etílico del ácido 3-(4-fluoro-benzoil)-1, 1 -dimetil-1,2,3,6,7,8,9,10-octahidro-azepin[4,5-b]indol-5-carboxílico, isopropilamida del ácido 3-(4-fluoro-benzoil)-1,1-dimetil-1,2,3,6-tetrahidro-azepin[4,5-b]indol-5-carboxílico,
éster etílico del ácido 3-(4-fluoro-benzo¡l)-1,1-d¡met¡l-9-(3-met¡l-but¡rilam¡no)-1,2,3,6-tetrah¡dro-azep¡n[4,5-b]¡ndol-5-carboxílico,
éster etílico del ácido 3-(4-fluoro-benzoil)-1,1-dimetil-9-fenilacetilamino-1,2,3,6-tetrahidro-azepin[4,5-b]indol-5-carboxílico,
éster etílico del ácido 3-(4-fluoro-benzoil)-1, 1 -dimetil-1,2,3,6,7,8,9,10-octahidro-azepin[4,5-b]indol-5-carboxílico, éster etílico del ácido 3-(4-fluoro-benzoil)-1,2,3,4,5,6,7,8,9,10-decahidro-azepin[4,5-b]indol-5-carboxílico, éster etílico del ácido 3-(4-fluoro-benzoil)-1,2,3,6,7,8,9,10-octahidro-azepin[4,5-b]indol-5-carboxílico, ciclobutilamida del ácido 3-(4-fluoro-benzoil)-1,2,3,6-tetrahidro-azepin[4,5-b]indol-5-carboxílico,
ciclobutilamida del ácido 3-(4-fluoro-benzoil)-2-metil-1,2,3,6-tetrahidro-azepin[4,5-b]indol-5-carboxílico,
éster 2-etílico éster 8-isopropílico del ácido 6-(3,4-difluoro-benzoil)-1,4,4-trimetil-1,4,5,6-tetrahidro-pirrol[2,3-d]azepin-2.8- dicarboxílico,
éster 2-etílico éster 8-isopropílico del ácido 6-(3,4-difluoro-benzoil)-4,4-dimetil-1,4,5,6-tetrahidro-pirrol[2,3-d]azepin-2.8- dicarboxílico,
éster dimetílico del ácido 6-(3,4-difluoro-benzoil)-4,4-dimetil-1,4,5,6-tetrahidro-pirrol[2,3-d]azepin-2,8-dicarboxílico, éster dietílico del ácido 6-(3,4-difluoro-benzoil)-4,4-dimetil-1,4,5,6-tetrahidro-pirrol[2,3-d]azepin-2,8-dicarboxílico, éster etílico del ácido 6-(3,4-difluoro-benzoil)-4,4-dimetil-5,6-dihidro-4H-tieno[2,3-d]azepin-8-carboxílico, éster etílico del ácido 6-(3,4-difluoro-benzoil)-5,6-dihidro-4H-tieno[2,3-D]azepin-8-carboxílico,
éster etílico del ácido 6-(4-fluoro-benzoil)-3,6,7,8-tetrahidro-imidazo[4,5-D]azepin-4-carboxílico,
éster etílico del ácido 9-(1-bencil-3,3-dimetil-ureido)-3-(4-fluoro-benzoil)-1,1-dimetil-1,2,3,6-tetrahidro-azepin[4,5-b]indol-5-carboxílico,
éster etílico del ácido 9-(2,2-dimetil-propionilamino)-3-(4-fluoro-benzoil)-1,1-dimetil-1,2,3,6-tetrahidro-azepin[4,5-b]indol-5-carboxílico,
éster etílico del ácido 9-(acetil-metil-amino)-3-(4-fluoro-benzoil)-1,1-dimetil-1,2,3,6-tetrahidro-azepin[4,5-b]indol-5-carboxílico,
éster etílico del ácido 9-[bencil-(2-tiofen-2-il-acetil)amino]-3-(4-fluoro-benzoil)-1, 1 -dimetil-1,2,3,6-tetrahidro-azepin[4,5-b]indol-5-carboxílico,
éster etílico del ácido 9-dimetil-amino-3-(4-fluoro-benzoil)-1,1-dimetil-1,2,3,6-tetrahidro-azepin[4,5-b]indol-5-carboxílico,
éster etílico del ácido 9-fluoro-3-(3,4-difluoro-benzoil)-1,1-dimetil-1,2,3,6-tetrahidro-azepin[4,5-b]indol-5-carboxílico, isopropilamida del ácido 9-fluoro-3-(3,4-difluoro-benzoil)-1,1-dimetil-1,2,3,6-tetrahidro-azepin[4,5-b]indol-5-carboxílico,
éster etílico del ácido 9-fluoro-3-(4-fluoro-benzoil)-1, 1 -dimetil-1,2,3,6-tetrahidro-azepin[4,5-b]indol-5-carboxílico, éster isopropílico del ácido 9-fluoro-3-(4-fluoro-benzoil)-1,1-dimetil-1,2,3,6-tetrahidro-azepin[4,5-b]indol-5-carboxílico, éster etílico del ácido 9-fluoro-3-ciclohexanocarbonil-1, 1 -dimetil-1,2,3,6-tetrahidro-azepin[4,5-b]indol-5-carboxílico, ciclobutil 3-(3,4-difluoro-benzoil)-1, 1 -dimetil-1,2,3,6-tetrahidro-azepin[4,5-b]indol-5-carboxamida,
dietil 3-(4-fluoro-benzoil-1,2,3,6-tetrahidro-azepin[4,5-b]indol-2,5-dicarboxilato,
etil 1, 1 -dimetil-1,2,3,6-tetrahidro-azepin[4,5-b]indol5-carboxilato,
etil 1,1-dimetil-3-(4-fluoro-benzoil)-1,2,3,6-tetrahidro-azepin[4,5-b]indol-5-carboxilato,
etil 3-(3,4-difluoro-benzoil)-1,1-dimetil-1,2,3,6-tetrahidro-azepin[4,5-b]indol-5-carboxilato,
etil 3-(3,4-difluoro-benzoil)-1 -metil-1,2,3,6-tetrahidro-azepin[4,5-b]indol-5-carboxilato,
etil 3-(4-cloro-benzoil)-1,1-dimetil-1,2,3,6-tetrahidro-azepin[4,5-b]indol-5-carboxilato,
etil 3-(4-cloro-benzoil)-1 -metil-1,2,3,6-tetrahidro-azepin[4,5-b]indol-5-carboxilato,
etil 3-(4-fluoro-benzoil)-1,2,3,6-tetrahidro-azepin[4,5-b]indol-5-carboxilato,
etil 3-(4-fluoro-benzoil)-1 -metil-1,2,3,6-tetrahidro-azepin[4,5-b]indol-5-carboxilato,
isopropil 3-(3,4-difluoro-benzoil)-1,1-dimetil-1,2,3,6-tetrahidro-azepin[4,5-b]indol-5-carboxilato,
isopropil 3-(3,4-difluoro-benzoil)-1-metil-1,2,3,6-tetrahidro-azepin[4,5-b]indol-5-carboxilato,
n-propil 3-(4-fluoro-benzoil)-2-metil-1,2,3,6-tetrahidro-azepin[4,5-b]indol-5-carboxilato, y
n-propil 3-(4-fluoro-benzoil)-2-metil-8-fluoro-1,2,3,6-tetrahidro-azepin[4,5-b]indol-5-carboxilato.
En algunos aspectos, el agonista de FXR se selecciona del grupo que consiste en los compuestos seleccionados a partir de los compuestos descritos en el documento WO2013037482, es decir:
ácido 4-(((6— ((5-ciclopropil-3-(2,6-diclorofenil)isoxazol-4-il)metoxi)-2-(trifluorometil)piridin-3-il)(metil)amino)metil)benzoico,
ácido 3-(2-(2-cloro-4-((5-ciclopropil-3-(2,6-diclorofenil)isoxazol-4-il)metoxi)fenil)ciclopropil)benzoico,
ácido 4-(2-(2-cloro-4-((5-ciclopropil-3-(2,6-diclorofenil)isoxazol-4-il)metoxi)fenil)ciclopropil)benzoico,
ácido 5-(2-(2-cloro-4-((5-ciclopropil-3-(2,6-diclorofenil)isoxazol-4-il)metoxi)fenil)ciclopropil)-1-isopropil-1 H-pirazol-3-carboxílico,
ácido 6-(2-(2-cloro-4-((5-ciclopropil-3-(2,6-diclorofenil)isoxazol-4-il)metoxi)fenil)ciclopropil)-1-metil-1 H-indazol-3-carboxílico,
ácido 6-(2-(2-cloro-4-((5-ciclopropil-3-(2,6-diclorofenil)isoxazol-4-il)metoxi)fenil)ciclopropil)-1-isopropil-1 H-indazol-3-carboxílico,
ácido 3-(3-(2-cloro-4-((5-ciclopropil-3-(2,6-diclorofenil)isoxazol-4-il)metoxi)fenil)-3-hidroxiciclobutil)benzoico, ácido 5-(3-(2-cloro-4-((5-ciclopropil-3-(2,6-diclorofenil)isoxazol-4-il)metoxi)fenil)-3-hidroxiciclobutil)-1 -isopropil-1 H-pirazol-3-carboxílico,
ácido 6-(3-(2-cloro-4-((5-ciclopropil-3-(2,6-diclorofenil)isoxazol-4-il)metoxi)fenil)-3-hidroxiciclobutil)-1-metil-1 H-indazol-3-carboxílico,
ácido 4-(3-(2-cloro-4-((5-ciclopropil-3-(2,6-diclorofenil)isoxazol-4-il)metoxi)fenil)-3-hidroxiciclobutil)benzoico, ácido 3-(3-(2-cloro-4-((5-ciclopropil-3-(2,6-diclorofenil)isoxazol-4-il)metoxi)fenil)-3-hidroxiazetidin-1-il)benzoico, y ácido 5-(3-(2-cloro-4-((5-ciclopropil-3-(2,6-diclorofenil)isoxazol-4-il)metoxi)fenil)-3-hidroxiazetidin-1-il)nicotínico. Los agonistas de FXR adicionales útiles en la presente descripción se pueden identificar de forma rutinaria por los expertos en la técnica basándose en los ensayos como los descritos en PCT/US99/30947. Normalmente, los agonistas de FXR se identifican usando un ensayo de péptido-receptor nuclear. Este ensayo utiliza la transferencia de energía de resonancia de fluorescencia (FRET) y se puede usar para probar si los ligandos teóricos se unen a FXR. El ensayo FRET se basa en el principio de que los ligandos inducen cambios conformacionales en los receptores nucleares que facilitan las interacciones con las proteínas co-activadoras requeridas para la activación transcripcional. En FRET, una molécula donante fluorescente transfiere energía a través de una interacción dipolo-dipolo no radiactivo a una molécula aceptora (que suele ser una molécula fluorescente).
Normalmente, el agonista de FXR de la descripción se administra al sujeto en una cantidad terapéuticamente eficaz. Por una “cantidad terapéuticamente eficaz” del agonista de FXR como se ha descrito anteriormente se entiende una cantidad suficiente del agonista de FXR para tratar una infección por el virus de la hepatitis B a una relación beneficio/riesgo razonable aplicable a cualquier tratamiento médico. Sin embargo, se entenderá que el médico que trata decidirá el uso diario total de los compuestos y composiciones de la presente descripción dentro del alcance del buen juicio médico. El nivel de dosis específico terapéuticamente eficaz para cualquier paciente particular dependerá de una variedad de factores que incluyen el trastorno que se está tratando y la gravedad del trastorno; la actividad del compuesto específico empleado; la composición específica empleada, la edad, el peso corporal, la salud general, el sexo y la dieta del paciente; el tiempo de administración, la ruta de administración y la velocidad de excreción del compuesto específico empleado; la duración del tratamiento; fármacos usados en combinación con el agonista específico empleado; y factores similares bien conocidos en las técnicas médicas. Por ejemplo, está bien dentro de la experiencia de la técnica empezar con dosis del compuesto a niveles más bajos que los requeridos para lograr el efecto terapéutico deseado y aumentar gradualmente la dosis hasta que se logre el efecto deseado. Sin embargo, la dosis diaria de los productos puede variar en un amplio rango de 0,01 a 1.000 mg por adulto por día. Preferiblemente,
las composiciones contienen 0,01,0,05, 0,1,0,5, 1,0, 2,5, 5,0, 10,0, 15,0, 25,0, 50,0, 100, 250 y 500 mg del ingrediente activo para el ajuste sintomático de la dosis al paciente a tratar. Típicamente, un medicamento contiene de aproximadamente 0,01 mg a aproximadamente 500 mg del ingrediente activo, preferiblemente de 1 mg a aproximadamente 100 mg del ingrediente activo. Normalmente se suministra una cantidad eficaz del fármaco a un nivel de dosificación de 0,0002 mg/kg a aproximadamente 20 mg/kg de peso corporal por día, especialmente de aproximadamente 0,001 mg/kg a 7 mg/kg de peso corporal por día.
Se puede administrar cualquiera de los dos regímenes de tratamiento anteriores a personas que han sido diagnosticadas con una infección por VHB. Cualquiera de los regímenes de tratamiento anteriores se puede administrar a personas que han fracasado en tratamientos anteriores para la infección por VHB (pacientes con fracaso de tratamiento). “Pacientes con fracaso del tratamiento” como se usa en esta memoria se refiere generalmente a pacientes infectados por VHB que no respondieron a la terapia previa para el VHB (denominados “no respondedores”) o que inicialmente respondieron a la terapia anterior pero en los que no se mantuvo la respuesta terapéutica anterior (denominados como “que recaen”). La terapia anterior y disponible en la actualidad puede incluir generalmente tratamiento con fármacos antivirales como lamivudina (Epivir), adefovir (Hepsera), tenofovir (Viread), telbivudina (Tyzeka) y entecavir (Baraclude), y los dos moduladores del sistema inmune interferón alfa-2a, interferón alfa-2a PEGilado (Pegasys) e interferón alfa-2b (ViraferonPeg ou Introna).
En particular, el agonista de FXR de acuerdo con la descripción se puede administrar al sujeto en combinación con la terapia actualmente disponible, que incluye el tratamiento con fármacos antivirales como los inhibidores de la transcriptasa inversa, lamivudina (Epivir), adefovir (Hepsera), tenofovir (Viread), telbivudina (Tyzeka) y entecavir (Baraclude) y como moduladores del sistema inmune, interferón alfa-2a, interferón alfa-2a PEGlilado (Pegasys) o interferón alfa-2b (ViraferonPeg ou Introna).
El agonista de FXR de la descripción se puede combinar con excipientes farmacéuticamente aceptables y, opcionalmente, con matrices de liberación sostenida, como polímeros biodegradables, para formar composiciones farmacéuticas.
“Farmacéuticamente” o “farmacéuticamente aceptable” se refiere a entidades y composiciones moleculares que no producen una reacción adversa, alérgica u otra reacción inapropiada cuando se administran a un mamífero, especialmente a un ser humano, según sea apropiado. Un vehículo o excipiente farmacéuticamente aceptable se refiere a un sólido no tóxico, semi-sólido o líquido de relleno, diluyente, material de encapsulación o auxiliar de formulación de cualquier tipo.
En las composiciones farmacéuticas de la presente descripción para administración oral, sublingual, subcutánea, intramuscular, intravenosa, trans-dérmica, local o rectal, el principio activo, solo o en combinación con otro principio activo, se puede administrar en forma de administración unitaria, como una mezcla con soportes farmacéuticos convencionales, a animales y a seres humanos. Las formas de administración unitaria adecuadas comprenden formas por vía oral como tabletas, cápsulas de gel, polvos, gránulos y suspensiones o soluciones orales, formas de administración sublingual y bucal, aerosoles, implantes, formas de administración subcutánea, trans-dérmica, tópica, intraperitoneal, intramuscular, intravenosa, sub-dérmica, trans-dérmica, intratecal e intranasal y formas de administración rectal.
En particular, las composiciones farmacéuticas contienen vehículos que son farmacéuticamente aceptables para una formulación capaz de ser inyectada. Estas pueden ser en particular soluciones salinas isotónicas, estériles (fosfato monosódico o disódico, cloruro de sodio, potasio, calcio o magnesio y similares o mezclas de tales sales), o composiciones secas, especialmente liofilizadas, que tras la adición, dependiendo del caso, de agua esterilizada o suero fisiológico, permiten la reconstitución de soluciones inyectables.
Las formas farmacéuticas adecuadas para uso inyectable incluyen soluciones o dispersiones acuosas estériles; formulaciones que incluyen aceite de sésamo, aceite de cacahuete o propilén glicol acuoso; y polvos estériles para la preparación extemporánea de soluciones o dispersiones inyectables estériles. En todos los casos, la forma debe ser estéril y debe ser fluida en la medida en que exista una fácil capacidad de inyección. Debe ser estable en las condiciones de fabricación y almacenamiento y debe preservarse de la acción contaminante de microorganismos, como bacterias y hongos.
Las soluciones que comprenden compuestos de la descripción como base libre o sales farmacológicamente aceptables se pueden preparar en agua mezcladas adecuadamente con un tensioactivo, como hidroxipropilcelulosa. También se pueden preparar dispersiones en glicerol, polietilén glicoles líquidos y mezclas de estos y en aceites. En condiciones normales de almacenamiento y uso, estas preparaciones contienen un conservante para prevenir el crecimiento de microorganismos.
El agonista de FXR de la descripción se puede formular en una composición en una forma neutra o de sal. Las sales farmacéuticamente aceptables incluyen las sales de adición de ácido (formadas con los grupos amino libres de la proteína) y que se forman con ácidos inorgánicos como, por ejemplo, ácidos clorhídrico o fosfórico, o como ácidos orgánicos como acético, oxálico, tartárico, mandélico, y similares. Las sales formadas con los grupos carboxilo libres
también se pueden derivar de bases inorgánicas como, por ejemplo, hidróxidos de sodio, potasio, amonio, calcio o férrico, y con bases orgánicas como isopropilamina, trimetilamina, histidina, procaína y similares.
El vehículo también puede ser un disolvente o medio de dispersión que contenga, por ejemplo, agua, etanol, poliol (por ejemplo, glicerol, propilén glicol, y polietilén glicol líquido, y similares), mezclas adecuadas de estos, y aceites vegetales. Se puede mantener la fluidez adecuada, por ejemplo, mediante el uso de un recubrimiento, como lecitina, mediante el mantenimiento del tamaño de partícula requerido en el caso de dispersión y mediante el uso de tensioactivos. La prevención de la acción de microorganismos se puede conseguir mediante diversos agentes antibacterianos y antifúngicos, por ejemplo, parabenos, clorobutanol, fenol, ácido sórbico, timerosal, y similares. En muchos casos, será preferible incluir agentes isotónicos, por ejemplo, azúcares o cloruro sódico. La absorción prolongada de las composiciones inyectables se puede producir mediante el uso en las composiciones de agentes que retrasan la absorción, por ejemplo, monoestearato de aluminio y gelatina.
Las soluciones inyectables estériles se preparan incorporando los polipéptidos activos en la cantidad requerida en el disolvente apropiado con diversas proporciones de los otros ingredientes enumerados anteriormente, según se requiera, seguido de esterilización por filtración. Generalmente, las dispersiones se preparan incorporando los diversos ingredientes activos esterilizados en un vehículo estéril que contiene el medio de dispersión básico y los demás ingredientes requeridos de los enumerados anteriormente. En el caso de polvos estériles para la preparación de soluciones inyectables estériles, los métodos preferidos de preparación son técnicas de secado al vacío y liofilización que producen un polvo del ingrediente activo más cualquier ingrediente adicional deseado a partir de una solución previamente esterilizada filtrada de este.
T ras la formulación, las soluciones se administrarán de una forma compatible con la formulación de dosificación y en una cantidad que sea terapéuticamente eficaz. Las formulaciones se administran fácilmente en una variedad de formas de dosificación, como el tipo de soluciones inyectables descritas anteriormente, pero también se pueden emplear cápsulas de liberación de fármaco y similares.
Para la administración parenteral en una solución acuosa, por ejemplo, la solución se debe tamponar adecuadamente si es necesario, y el diluyente líquido se debe volver primero isotónico con solución salina o glucosa suficiente. Estas soluciones acuosas particulares son especialmente adecuadas para la administración intravenosa, intramuscular, subcutánea e intraperitoneal. A este respecto, los expertos en la técnica conocerán los medios acuosos estériles que se pueden emplear a la luz de la presente descripción. Por ejemplo, una dosis se podría disolver en 1 ml de solución isotónica de NaCl y agregarse a 1.000 ml de fluido de hipodermoclisis o inyectarse en el lugar de infusión propuesto. Se producirá necesariamente alguna variación en la dosificación dependiendo de la condición del sujeto a tratar. La persona responsable de la administración determinará, en cualquier caso, la dosis apropiada para el sujeto individual.
El agonista de FXR de la descripción se puede formular dentro de una mezcla terapéutica para que comprenda aproximadamente 0,0001 a 1,0 miligramos, o aproximadamente 0,001 a 0,1 miligramos, o aproximadamente 0,1 a 1,0 o incluso aproximadamente 10 miligramos por dosis más o menos. También se pueden administrar dosis múltiples.
Además, los compuestos de la descripción formulados para la administración parenteral, como inyección intravenosa o intramuscular, otras formas farmacéuticamente aceptables incluyen, p. ej., tabletas u otros sólidos para la administración oral; formulaciones liposomales; cápsulas de liberación prolongada; y cualquier otra forma actualmente usada.
La descripción se ilustrará de manera adicional mediante las siguientes figuras y ejemplos.
Figuras
Figura 1 Secreción de antígenos de superficie HBs (HBsAg) en el sobrenadante de la línea celular HepaRG infectada con VHB en presencia de moduladores de FXR.
Se infectaron células HepaRG diferenciadas con VHB (100 geq/célula durante 24 h), luego se trataron 3 veces sucesivas (días 4, 7 y 11 después de la infección) con moduladores de FXR a las concentraciones indicadas en pM. Se recogieron los sobrenadantes celulares 14 días después de la infección para la cuantificación de HBsAg (Architec Abbott).
Figura 2.- Secreción de antígenos de superficie (HBsAg), del núcleo (HBeAg) de VHB y ADN de VHB en el sobrenadante de HepaRG infectadas con VHB.
Se infectaron células HepaRG diferenciadas con VHB (100 geq/célula durante 24 h.), luego se trataron 3 veces sucesivas (días 4, 7 y 11 después de la infección) con agonistas y antagonistas de FXR o ácido biliar UDCA inactivo para FXR a las concentraciones indicadas (pM). Se recogieron los sobrenadantes celulares 14 días después de la infección para la cuantificación de HBsAg, HBeAg (Architec Abbott) o ADN de VHB mediante PCR cuantitativa usando cebadores de rcADN (n=3 ± SEM). A. Ambos agonistas de FXR, GW4064 y 6ECDCA, inhiben la secreción de HBsAg y HBeAg en el sobrenadante de una manera dependiente de la dosis, mientras que UDCA y 052EDL133 no tienen ningún efecto sobre la secreción de antígeno. B. Ambos agonistas de FXR, GW4064 y 6ECDCA, inhiben la secreción de partículas virales de VHB ADN positivas infecciosas en el sobrenadante de una manera dependiente de la dosis.
El UDCA y el 052EDL133 tienen un efecto nulo o limitado sobre la secreción del virión. C. El agonista de FXR PXL007 reprime HBsAg, HBeAg y el ADN de VHB de una manera dependiente de la dosis.
Figura 3.- Expresión de la proteína del núcleo de VHB (HBc) dentro de células HepaRG en presencia o no de agonistas de FXR.
Se crecieron células HepaRG diferenciadas sobre portas y se trataron como se describe en la leyenda de la Figura 1 (n=3 ± SEM). Se fijaron las células el día 14 después de la infección y se llevó a cabo la inmuno-citoquímica usando un anticuerpo anti-HBc. La microscopía de fluorescencia revela que los agonistas de FXR, GW4064 y 6ECDCA, reducen drásticamente la expresión de HBc en las células infectadas. El UDCA y el 052EDL133 no parecen modificar la expresión de HBc.
Figura 4.- Expresión de ARNm pre-genómico/pre-nuclear de VHB y de cccADN en la línea celular HepaRG infectada con VHB en presencia o no de agonistas de FXR.
Se infectaron células HepaRG diferenciadas y se trataron como se describe en la leyenda de la Figura 1. Las células se lisaron y se extrajo el ARN, luego se transcribió inversamente en ADNc para la PCR cuantitativa (qRT-PCR) (A) o se usó para el experimento en transferencia de Northern (B). Se repitió el mismo experimento y se extrajo el ADN. Después del tratamiento con ADNasa seguro para plásmidos, se cuantificó la expresión de cccADN mediante experimento de qPCR usando cebadores de cccADN específicos de VHB y la sonda TaqMan (n=3 ± SEM). (C). La cuantificación de cccADN se normalizó al número de genes de bglobina. Se cuantificaron los niveles de expresión de genes pre-genómicos de VHB, así como 3 genes de mantenimiento para la normalización (n=3 ± SEM). Ambos agonistas de FXR, GW4064 y 6ECDCA, inhiben la expresión del ARNm pre-genómico/pre-nuclear del VHB de una manera dependiente de la dosis. La reducción se confirma en la transferencia de Northern (banda de 3,4-3,5 Kb). La expresión de otros ARNm de VHB (S: 2,1-2,4 Kb; X: 0,7 Kb) también se reduce, como se ve en el gráfico de densitometría (n=3 ± SEM). Los niveles de cccADN también se redujeron en más del 50% después del tratamiento con agonistas de FXR.
Figura 5.- Efecto de la Ciclosporina A inhibidor de la entrada del VHB sobre la modulación de los agonistas de FXR de la secreción de HBsAg y HBeAg en el sobrenadante de células HepaRG infectadas con VHB.
Se infectaron y se trataron células HepaRG diferenciadas como se describió en la leyenda de la Figura 1. Además del protocolo habitual descrito anteriormente, las células se trataron con Ciclosporina (CyA) ya sea durante la infección con VHB (es decir, durante 24 h) o durante el primer tratamiento con agonistas de FXRa (es decir, durante 72 h; del día 4 al 7 después de la infección). Se recogieron los sobrenadantes celulares 14 días después de la infección para la cuantificación de HBsAg y HBeAg (n=3 ± SEM). A) El tratamiento con CyA durante la infección por VHB inhibe la entrada viral de una manera dependiente de la dosis y no altera la disminución de las secreciones de HBsAg y HBsAg después del tratamiento con agonistas de FXR. B) El tratamiento con CyA después de la infección no tiene ningún efecto en la secreción del antígeno del VHB, independientemente de la presencia o no de agonistas de FXR.
Figura 6.- Ensayo de co-inmunoprecipitación de las proteínas FXR y HBx
Se co-transfectaron células HEK293T con plásmidos que codifican las proteínas de fusión 3XF-HBx y Gluc-FXR. 48 horas después de la transfección se lisaron las células y se realizó la co-inmunoprecipitación con Dynabeads®Protein G previamente acoplada con anticuerpo anti-3XF. Los lisados celulares y los productos de co-inmunoprecipitación se analizaron mediante transferencia de Western; la expresión de FXR se detectó con anticuerpo anti-Gluc. La expresión de FXR en el control, Gluc-FXR solo, o en las células de prueba, la co-expresión de Gluc-FXR y 3XF-HBx fue similar como se muestra en la transferencia de western izquierda. Después de la inmunoprecipitación con anticuerpo anti-3XF, la proteína de fusión FXR se detectó de forma evidente en la condición de prueba y no en el control (transferencia de western derecha). Estas observaciones sugieren fuertemente una interacción entre la proteína vira1 HBx y el receptor nuclear FXR.
Figura 7.- Expresión de ARNm de FXR y dos de sus genes regulados
Se infectaron y se trataron células HepaRG diferenciadas como se describió en la leyenda de la Figura 1. Las células se lisaron y se extrajo el ARN, luego se sometió a transcripción inversa en ADNc para la qPCR. Se cuantificaron los niveles de expresión de 3 genes de interés: FXRa, SHP y APOA1, así como 3 genes de mantenimiento para la normalización (n=3 ± SEM). Los agonistas de FXR, GW4064 y 6ECDCA, inhiben la expresión del ARNm de FXR de una manera dependiente de la dosis. SHP y APOA1 son dos genes bajo la regulación de FXR: SHP se induce por FXR mientras que APOA1 se reprime. Aquí, la expresión del ARNm de SHP aumenta con los tratamientos con GW4064 y 6ECDCA, mientras que la expresión del ARNm de APOA1 disminuye. Esto sugiere una activación de FXR a pesar de su expresión reducida.
Figura 8.- Tratamiento conjunto del agonista de FXR con lamivudina, un potente inhibidor de la transcriptasa inversa análogo de nucleósido
Se infectaron y se trataron células HepaRG diferenciadas como se describió en la leyenda de la Figura 1. Se recogieron los sobrenadantes celulares 14 días después de la infección. (A) Cuantificación de la secreción de HBsAg y HBeAg.
(B) Cuantificación de partículas infecciosas secretadas mediante extracción de ADN y cuantificación por qPCR. El tratamiento con lamivudina a 10 pM tiene un efecto muy limitado sobre la secreción de antígenos de VHB, mientras que su efecto sobre la secreción de ADN de VHB es casi completo con una reducción del 97% del ADN de VHB en el sobrenadante celular.
Ejemplo:
Métodos:
La línea HepaRG derivada de un carcinoma hepatocelular humano se puede diferenciar y recuperar muchos rasgos fenotípicos de los hepatocitos después de las 4 semanas de cultivo en condiciones definidas (Hantz O. y cols., 2009. J Gen Virol 90: 127-135). Después de la diferenciación, estas células son susceptibles a la infección a un alto MOI de viriones de VHB producidos por la línea HepG2.2.15. En estas condiciones, se puede observar la producción viral en la segunda semana después de la infección. Este sistema permite el estudio de la mayoría de las etapas del ciclo de replicación viral, que incluyen la penetración dentro de la célula, la translocación del genoma viral al núcleo, la reparación y síntesis del cccADN, las transcripción de los ARNms pre-genómicos y virales , así como las etapas posteriores del ciclo de replicación con la síntesis de las proteínas virales, el ensamblaje y la secreción de los viriones infecciosos y la secreción de las proteínas virales HBs y HBe.
El sistema HepaRG permite, por lo tanto, el seguimiento de la secreción de HBsAg y HBeAg y el ADN incorporado del virión en el sobrenadante del cultivo celular después de la infección con suministro de viriones infecciosos de VHB preparados a partir de la línea celular HepG2.2.15. Este sistema permite también el seguimiento de la síntesis de los ARNms pre-genómicos y virales, así como de intermedios de replicación citoplásmica y cccADN. Se exploraron los efectos de las moléculas sobre la fisiología celular y las funciones de las células diferenciadas incluyendo la cuantificación de marcadores hepáticos como la albúmina y la apolipoproteína B. Se siguieron los efectos de los compuestos sobre la vía celular de los ácidos biliares mediante análisis y cuantificación del ARNm de FXR así como de los ARNms que codifican SHP y apoA1 cuya expresión está bajo el control de FXR.
Resultados:
Los agonistas de FXR son potentes inhibidores de la replicación del VHB:
Se probó primero un panel de moléculas, no descritas previamente y moduladores originales o de referencia de la actividad de FXR sobre la expresión de un gen reportero bajo el control de la región promotora Enh2/core del VHB que contiene dos elementos de respuesta a FXR en la línea celular Huh-7 como se describe en Ramiere C, y cols., 2008, J Virol; 82: 10832-10840. A continuación, las moléculas se clasificaron como agonistas o antagonistas de FXR en base al aumento o disminución de la expresión, respectivamente, del gen reportero bajo el control de transcripción de FXR. Algunas moléculas tenían un perfil intermedio, siendo moderadamente agonistas cuando se ensayaron por separado y antagonistas débiles cuando se ensayaron en competición frente a un agonista de referencia (datos no mostrados). Se evaluaron primero los compuestos más potentes y representativos por sus efecto sobre la síntesis y la secreción de HBsAg en el sobrenadante del cultivo del sistema de cultivo de células HepaRG infectadas de forma natural con VHB producido por HepG2.2.15 (figura 1). De manera inesperada, los antagonistas más potentes (es decir, 100ED0038, 100ED0136, 100ED0137, y 100ED0166), así como el antagonista de referencia 052EDL133 descrito en la patente WO 2007052843; Takeda Pharmaceutical Co. Ltd., Osaka, tuvieron poco o ningún efecto sobre la secreción de HBsAg. De manera sorprendente, el agonista GW4064, tal como se describe en la publicación PCT N°. WO 00/37077 o en US2007/0015796 tuvo un fuerte efecto y un efecto inhibidor dependiente de la dosis sobre la secreción de HBsAg (aproximadamente un 70% de inhibición a 10 pM. Agonistas parciales como PXL0914 (ácido 4-bromo-5-[4-(2-cloro-bencenosulfonil)-[1,4]diazepan-1 -il]-benzofuran-2-carboxílico de la patente WO2009127321), PXL0924 (ácido 5-[4-(2,6-dicloro-benzoil)-piperazin-1-il]-4-metil-benzofuran-2-carboxílico de la patente WO2009127321) y PXL0743 (ácido 4-bromo-5-[4-(2,6-dicloro-bencenosulfonilamino)-piperidin-1-il]-benzofuran-2-carboxílico de la patente WO2009127321) tuvieron un perfil intermedio de inhibición. Por lo tanto, algunas moléculas disminuyeron la producción de HBsAg de una manera dependiente de la dosis. Si las moléculas activas se clasificaran por su antagonista, agonista o agonista “parcial” mediante la prueba de detección en las células Huh-7 con el constructo del gen reportero, parece, contra todo pronóstico, que el efecto inhibidor sobre la producción de HBsAg creció con la tendencia de la molécula a ser un potente agonista de FXR.
Para confirmar este hallazgo, a continuación se probaron varias moléculas, el antagonista de referencia de FXR 052EDL133 (véase anteriormente), dos agonistas de FXR bien caracterizados, que pertenecen a una clase química diferente, GW4064 (véase anteriormente) y 6ECDCA (un derivado de sal biliar y potente agonista de FXR, actualmente en ensayo clínico para la cirrosis biliar primaria y la resistencia a insulina, véase anteriormente) y el análogo de sal biliar ácido ursodesoxicólico, que no es un ligando de FXR (Parks DJ1, y cols., Science. 1999 May 21; 284(5418): 1365-8. Makishima M1, y cols., Science. 1999 May 21; 284(5418): 1362-5). La Figura 2A muestra que solo GW4064 y 6ECDCA tenían un efecto inhibidor fuerte y dependiente de la dosis sobre la secreción de HBsAg y HBeAg en el sobrenadante de células infectadas HepaRG después de 10 días de tratamiento. La sal biliar de ursodesoxicolato no inhibió la secreción de la proteína viral en ninguna dosis y el antagonista de FXR 052EDL133 tuvo poco o ningún efecto. Se observaron hallazgos similares cuando se probó el efecto de estas moléculas sobre la secreción de ADN viral en el sobrenadante (Figura 2B). Se observó una fuerte inhibición, hasta del 80%, con los dos agonistas, mientras
que el UDCA no modificó la secreción del ADN viral. Sin embargo, cabe señalar, que el antagonista 052EDL133 redujo de manera moderada la cantidad de ADN viral secretado a 10 mM (cerca del 20% de inhibición). Finalmente, se probó en el mismo ensayo la actividad sobre la replicación viral de un agonista de FXR químicamente diferente, PXL007, identificado mediante el número de registro CAS 1192171-69-9 (descrito en el documento WO 2009127321). Este agonista de FXR también inhibió fuertemente la secreción de ADN y proteína virales (Figura 2C).
Además se exploró el efecto de GW4064 y 6ECDCA sobre la expresión celular de la proteína viral del núcleo HBc mediante inmunofluorescencia (Figura 3). De nuevo, ambos agonistas de FXR inhibieron fuertemente la expresión de HBc en células infectadas mientras que UDCA y 052EDL133 no modificaron de manera significativa la síntesis de HBc.
Finalmente, se cuantificó la cantidad de ARN viral mediante RT-PCR cuantitativa y transferencia de Northern en células infectadas tratadas o no con GW4064 y 6ECDCA así como las variaciones del reservorio de cccADN (Figura 4). La presencia de los dos ARN pre-nuclear de 3,4 y 3,5 y pre-genómico se redujo de una manera dependiente de la dosis por los agonistas de FXR hasta en un 75% (panel A) medido mediante RT-PCR cuantitativa. La presencia de las tres clases de ARNm viral, es decir, el ARNm pre-nuclear de 3,4 y 3,5 y pre-genómico, el ARNm de 2,1-2,4 S y el ARNm de 0,7 X, se redujo en un grado similar a 10 mM medido por transferencia de Northern (panel B). De manera interesante, el reservorio de cccADN también se redujo en más del 50% después del tratamiento con los dos agonistas a 10 mM (panel C).
Mecanismo de acción
Se identificó recientemente el péptido co-transportador de taurocolato de sodio (NTCP) como un receptor para HBsAg en la membrana plasmática baso-lateral de los hepatocitos. La expresión de NTCP es necesaria para la entrada del virus en los hepatocitos. El polipéptido co-transportador de taurocolato de sodio es un receptor funcional para el virus de la hepatitis B y D (Yan H. y cols., Elife (Cambridge). 2012 Nov 13; 1: e00049. doi: 10.7554/eLife.00049). El VHB y los ácidos biliares comparten un sitio de unión común en el NTCP y compiten por el receptor (Yan H. y cols., J Virol.
2014 Mar; 88(6): 3273-84. doi: 10.1128/JVI.03478-13. Epub 2014 Jan 3). Como los agonistas de FXR son moléculas que derivan directamente de los ácidos biliares o comparten determinantes moleculares comunes con los ácidos biliares, los agonistas de FXR podrían simplemente inhibir la entrada del virus a través de la competencia por el receptor. Por lo tanto, se probó el efecto de la adición a los agonistas de FXR de Ciclosporina A (CsA), una molécula que inhibe la ingesta de ácidos biliares mediada por NTCP, se une a NTCP en un sitio idéntico o superpuesto con el sitio de unión del péptido pre-S1 (Nkongolo S, y cols., J Hepatol. 2014 Apr; 60(4): 723-31. doi: 10.1016/j.jhep.2013.11.022. Epub 2013 Dec 1). Cuando se introdujeron concentraciones crecientes de CsA en el medio de cultivo durante la infección, se observó una competición dependiente de la dosis con la entrada del VHB con una inhibición de la secreción de HBsAg y HBeAg como se esperaba. El tratamiento con GW4064 o 6ECDCA redujo aún más la secreción de las proteínas virales (Figura 5A). Por el contrario, la adición de CsA después del periodo de infección no tuvo efecto sobre la replicación del VHB con una secreción conservada de HBsAg y HBeAg, ni modificó el efecto de los agonistas de FXR (Figura 5B). Teniendo en cuenta, como se informó anteriormente, que hay poca o ninguna propagación viral durante el cultivo en este sistema, se concluyó que la actividad antiviral de los agonistas de FXR no está relacionada con una inhibición directa de NTCP, sino que modula las etapas posteriores del ciclo de infección.
A continuación, se investigó si las proteínas virales podrían interferir con FXR mediante co-inmunoprecipitación usando proteínas virales y FXR con marcajes. Se encontró que la proteína viral HBx y FXR podían inmunoprecipitar mediante un anticuerpo dirigido frente a una o la otra proteína (Figura 6). Estos datos sugieren una interacción entre HBx y FXR, lo que refuerza la hipótesis de que el virus regula estrechamente la actividad de FXR.
A continuación se investigó el efecto de los agonistas de FXR sobre el nivel de expresión del ARNm que codifica el propio FXR así como SHP y ApoA1, dos genes cuyas expresiones están, respectivamente, bajo el control positivo y negativo de FXR. Se encontró que el tratamiento de 10 días con agonistas de FXR, GW4064 y 6ECDCA, aumentó la expresión del ARNm de SHP y disminuyó el ARNm de ApoA1, lo que indicaba que, de hecho, los agonistas de FXR aumentaron la actividad de FXR (Figura 7). De manera interesante, la expresión del ARNm de FXR también se reprimió fuertemente por ambos agonistas, probablemente como resultado del bucle de control negativo dependiente de SHP en la expresión de FXR. Por tanto, el tratamiento con agonistas de FXR modifican significativamente y de manera duradera el metabolismo de los ácidos biliares con una actividad de FXR aumentada junto con una expresión de FXR disminuida.
Efecto del tratamiento combinado con agonista de FXR e inhibidor de la transcriptasa inversa sobre la replicación del VHB.
Por lo tanto, los agonistas de FXR parecen reprimir la replicación del VHB en etapas que ocurren después de la entrada viral y principalmente sobre la estabilidad y expresión del reservorio de cccADN, por lo tanto antes de la etapa de la transcripción inversa. Por tanto, se probó el efecto del tratamiento de combinación de células HepaRG infectadas con VHB sobre la replicación viral (Figura 8). Se observó que el tratamiento con el inhibidor de la transcriptasa inversa análogo de nucleósido, lamivudina, incluso a alta concentración (10 mM con un IC50 de 6 nM, Lada O, y cols. Antivir Ther. 2004 Jun; 9(3): 353-63) solamente reprimió débilmente la secreción de HBsAg y HBeAg pero disminuyó de
manera muy eficaz la secreción de viriones de VHB ADN positivos como se esperaba. En esta condición, la adición del agonista de FXR no pareció disminuir aún más la secreción de ADN viral, pero reprimió de manera potente la síntesis y secreción de proteínas virales.
Discusión:
Se demostró que el FXR es un factor del huésped esencial en el desarrollo del VHB en los hepatocitos y que, de manera inesperada, los agonistas de FXR son inhibidores más potentes que los antagonistas de la replicación del VHB en las líneas celulares HepaRG. Esta actividad antiviral se demostró con agonistas de FXR estructuralmente muy diversos y selectivos, GW4064, PXL007 (molécula que tiene el número de registro CAS: 1192171-69-9), el derivado de ácido biliar 6ECDCA y otros. Esto reduce la probabilidad de un efecto “fuera de diana”. Los agonistas de FXR parecen actuar primariamente sobre la transcripción y la expresión de ARNms virales a partir del mini-cromosoma viral y sobre la estabilidad del cccADN. En general, los agonistas de FXR, además de reducir la replicación del ADN viral y la producción de viriones infecciosos, un efecto que se puede lograr de manera eficaz y segura con los inhibidores de la polimerasa de la transcriptasa inversa, tienen la capacidad única de disminuir la síntesis y secreción de las proteínas virales y reducir el tamaño del reservorio de cccADN. Estos dos efectos tardíos no se logran con los inhibidores de la polimerasa y solo se pueden alcanzar en un bajo porcentaje de pacientes tratados con interferones. Reducir la secreción de proteínas virales y el reservorio de cccADN son dos objetivos principales para curar la infección por VHB ya que, por un lado, se ha demostrado que las proteínas virales amortiguan la respuesta inmune innata, principalmente a través de la interacción con los TLR y mantienen un estado de tolerancia inmune frente al virus, y, por otro lado, la persistencia y latencia virales dependen de la presencia continua del cccADN.
La persistencia de la replicación del VHB también requiere la presencia de un entorno celular de apoyo que proporcione, en particular, una maquinaria celular transcripcional activa para la expresión de los genes virales. La regulación de la actividad de FXR por parte del virus puede ser parte de la estrategia viral para controlar su propia replicación. De hecho, la competencia entre los viriones del VHB y los ácidos biliares por el NTCP disminuye el conjunto de ácidos biliares intracelulares con las consecuencias posteriores de una disminución de la actividad de FXR y un mayor nivel de expresión de FXR (Oehler N, y cols., Hepatology. 2014 Apr 8. doi: 10.1002/hep.27159.
[Publicación electrónica antes de la publicación]). El tratamiento con agonistas de FXR demostró revertir la modificación del metabolismo de los ácidos biliares inducida por el virus, que, por lo tanto, aparece como una condición beneficiosa para mantener la replicación viral.
El descubrimiento del efecto antiviral del 6ECDCA, una molécula en desarrollo clínico en dos indicaciones separadas (es decir, cirrosis biliar primaria y resistencia a insulina), con buena tolerancia durante el tratamiento a largo plazo, ofrece la oportunidad de “reposicionar” la molécula en el tratamiento de la infección por VHB. En conclusión, se han identificado nuevas moléculas (es decir, agonistas de FXR) que regulan (reducen) la infección por VHB. Esto debería permitir la selección de candidatos que se podrían probar en un modelo de ratón o directamente en seres humanos con agonistas de FXR que ya se encuentran en ensayos clínicos.
Claims (6)
1. Un agonista del receptor farnesoide X (FXR) para usar en el tratamiento de la infección por el virus de la hepatitis B (VHB) en un sujeto que lo necesite, seleccionado del grupo que consiste en el compuesto identificado por el NÚMERO DE REGISTRO CAS 1192171 -69-9, GW4064 de fórmula
y el ácido 6-etil-quenodesoxicólico
2. El agonista del receptor farnesoide X (FXR) para usar de acuerdo con la reivindicación 1, en donde el sujeto está infectado con cualquier genotipo del virus de la hepatitis B que incluye los genotipos A, B, C, o D.
3. El agonista del receptor farnesoide X (FXR) para usar de acuerdo con la reivindicación 1, en donde el sujeto padece una infección crónica por VHB.
4. El agonista del receptor farnesoide X (FXR) para usar de acuerdo con la reivindicación 1, en donde el sujeto no ha respondido a un tratamiento previo para la infección por VHB.
5. El agonista del receptor farnesoide X (FXR) para usar de acuerdo con la reivindicación 4, en donde el tratamiento previo se selecciona del grupo que consiste en fármacos antivirales como lamivudina (Epivir), adefovir (Hepsera), tenofovir (Viread), telbivudina (Tyzeka) y entecavir (Baraclude), y dos moduladores del sistema inmune interferón alfa-2a e interferón alfa-2a PEGilado (Pegasys) o interferón alfa-2b (ViraferonPeg ou Introna).
6. El agonista del receptor farnesoide X (FXR) para usar de acuerdo con la reivindicación 1, en donde el agonista de FXR se administra en combinación con un tratamiento seleccionado del grupo que consiste en fármacos antivirales como lamivudina (Epivir), adefovir (Hepsera), tenofovir (Viread), telbivudina (Tyzeka) y entecavir (Baraclude), y dos moduladores del sistema inmune interferón alfa-2a e interferón alfa-2a PEGilado (Pegasys) o interferón alfa-2b (ViraferonPeg ou Introna).
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