ABSTRACT
Three unreported analogues of 4-[1-(3,5,5,8,8-pentamethyl-5-6-7-8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), otherwise known as bexarotene, as well as four novel analogues of (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalen-7-yl)-4-hydroxyphenyl)acrylic acid (CD3254), are described and evaluated for their retinoid X receptor (RXR) selective agonism. Compound 1 has FDA approval as a treatment for cutaneous T-cell lymphoma (CTCL), although treatment with 1 can elicit side-effects by disrupting other RXR-heterodimer receptor pathways. Of the seven modeled novel compounds, all analogues stimulate RXR-regulated transcription in mammalian 2 hybrid and RXRE-mediated assays, possess comparable or elevated biological activity based on EC50 profiles, and retain similar or improved apoptotic activity in CTCL assays compared to 1. All novel compounds demonstrate selectivity for RXR and minimal crossover onto the retinoic acid receptor (RAR) compared to all-trans-retinoic acid, with select analogues also reducing inhibition of other RXR-dependent pathways (e.g., VDR-RXR). Our results demonstrate that further improvements in biological potency and selectivity of bexarotene can be achieved through rational drug design.
Subject(s)
Coumaric Acids/pharmacology , Retinoid X Receptors/agonists , Tetrahydronaphthalenes/pharmacology , Coumaric Acids/chemical synthesis , Coumaric Acids/chemistry , Crystallography, X-Ray , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Tetrahydronaphthalenes/chemical synthesis , Tetrahydronaphthalenes/chemistryABSTRACT
The synthesis of halogenated analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), known commonly as bexarotene, and their evaluation for retinoid X receptor (RXR)-specific agonist performance is described. Compound 1 is FDA approved to treat cutaneous T-cell lymphoma (CTCL); however, bexarotene treatment can induce hypothyroidism and elevated triglyceride levels, presumably by disrupting RXR heterodimer pathways for other nuclear receptors. The novel halogenated analogues in this study were modeled and assessed for their ability to bind to RXR and stimulate RXR homodimerization in an RXRE-mediated transcriptional assay as well as an RXR mammalian-2-hybrid assay. In an array of eight novel compounds, four analogues were discovered to promote RXR-mediated transcription with EC(50) values similar to that of 1 and are selective RXR agonists. Our approach also uncovered a periodic trend of increased binding and homodimerization of RXR when substituting a halogen atom for a proton ortho to the carboxylic acid on 1.
Subject(s)
Anticarcinogenic Agents/chemistry , Anticarcinogenic Agents/pharmacology , Retinoid X Receptors/agonists , Tetrahydronaphthalenes/chemistry , Tetrahydronaphthalenes/pharmacology , Animals , Apoptosis/drug effects , Bexarotene , Cell Line, Tumor , Halogenation , Humans , Lymphoma, T-Cell, Cutaneous/drug therapy , Lymphoma, T-Cell, Cutaneous/metabolism , Molecular Docking Simulation , Neoplasms/drug therapy , Neoplasms/metabolism , Protein Multimerization/drug effects , Retinoid X Receptors/chemistry , Retinoid X Receptors/metabolismABSTRACT
Se realizó un estudio descriptivo transversal para evaluar el cumplimiento del tratamiento intercrisis de los 173 pacientes asmáticos dispensarizados en dos consultorios del médico de la familia del Policlínico Ignacio Agramonte del municipio Camagüey, durante el año 2003. Las historias clínicas individuales y familiares constituyeron la fuente primaria de los datos, se confeccionó una encuesta al efecto con las variables estudiadas: grupos de edades, sexo, grado de severidad, cumplimiento del tratamiento intercrisis, frecuencia de síntomas, asistencia al servicio de urgencia e ingresos hospitalarios, las que fueron procesadas automatizadamente. Predominaron los asmáticos clasificados como intermitentes leves (43.4 por ciento), el 72.3 por ciento cumplieron mal el tratamiento intercrisis y de ellos, el 28 por ciento presentaron síntomas continuos. En las casi tres cuartas partes de los asmáticos que cumplieron mal el tratamiento fueron frecuentes la presencia de síntomas, la asistencia al servicio de urgencia y los ingresos hospitalarios(AU)
Subject(s)
Humans , Status Asthmaticus , Physicians, Family , Cross-Sectional Studies , Epidemiology, DescriptiveABSTRACT
Se realizó un estudio descriptivo transversal para evaluar el cumplimiento del tratamiento intercrisis de los 173 pacientes asmáticos dispensarizados en dos consultorios del médico de la familia del Policlínico Ignacio Agramonte del municipio Camagüey, durante el año 2003. Las historias clínicas individuales y familiares constituyeron la fuente primaria de los datos, se confeccionó una encuesta al efecto con las variables estudiadas: grupos de edades, sexo, grado de severidad, cumplimiento del tratamiento intercrisis, frecuencia de síntomas, asistencia al servicio de urgencia e ingresos hospitalarios, las que fueron procesadas automatizadamente. Predominaron los asmáticos clasificados como intermitentes leves (43.4 por ciento), el 72.3 por ciento cumplieron mal el tratamiento intercrisis y de ellos, el 28 por ciento presentaron síntomas continuos. En las casi tres cuartas partes de los asmáticos que cumplieron mal el tratamiento fueron frecuentes la presencia de síntomas, la asistencia al servicio de urgencia y los ingresos hospitalarios