RESUMEN
Computational analysis of the ligand binding pocket of the three PPAR receptor subtypes was utilized in the design of potent PPARalpha agonists. Optimum PPARalpha potency and selectivity were obtained with substituents having van der Waals volume around 260. Compound 6 had a PPARalpha potency of 0.002 microM and a selectivity ratio to PPARgamma and PPARdelta of 410 and 2000, respectively.
Asunto(s)
Diseño de Fármacos , PPAR alfa/agonistas , Fenilpropionatos/química , Fenilpropionatos/farmacología , Animales , Computadores , Cristalografía , Ligandos , PPAR alfa/química , Fenilpropionatos/síntesis químicaRESUMEN
Two potent nonselective, but PPARalpha-preferring, PPAR agonists 5 and 6 were designed and synthesized in high yields. The concept of dimeric ligands in transcription factors was investigated by synthesizing and testing the corresponding dimers 7, 8a, and 8b in PPAR transactivation assays. The three dimeric ligands all showed agonist activity on all three PPAR receptor subtypes, but with different profiles compared to the monomers 5 and 6. Despite breaking all the "rule of five" criteria, the dimers had excellent oral bioavailability and pharmacokinetic properties, resulting in good in vivo efficacy in db/db mice. X-ray crystal structure and modeling experiments suggested that the dimers interacted with the AF-2 helix as well as with amino acid residues in the lipophilic pocket close to the receptor surface.
Asunto(s)
Alquenos/síntesis química , Propionatos/síntesis química , Receptores Citoplasmáticos y Nucleares/agonistas , Factores de Transcripción/agonistas , Alquenos/farmacocinética , Alquenos/farmacología , Secuencia de Aminoácidos , Animales , Sitios de Unión , Disponibilidad Biológica , Línea Celular , Cristalografía por Rayos X , Dimerización , Humanos , Ligandos , Masculino , Ratones , Modelos Moleculares , Datos de Secuencia Molecular , Propionatos/farmacocinética , Propionatos/farmacología , Ratas , Receptores Citoplasmáticos y Nucleares/química , Receptores Citoplasmáticos y Nucleares/metabolismo , Alineación de Secuencia , Estereoisomerismo , Factores de Transcripción/química , Factores de Transcripción/metabolismo , Activación TranscripcionalRESUMEN
Using a known dual PPARalpha/gamma activator (5) as a structural template, SAR evaluations led to the identification of triple PPARalpha/gamma/delta activators (18-20) with equal potency and efficacy on all three receptors. These compounds could become useful tools for studying the combined biological effects of PPARalpha/gamma/delta activation.
Asunto(s)
Receptores Citoplasmáticos y Nucleares/efectos de los fármacos , Factores de Transcripción/efectos de los fármacos , Animales , Glucemia/metabolismo , Prueba de Tolerancia a la Glucosa , Insulina/sangre , Masculino , Ratones , Modelos Moleculares , Conformación Molecular , Receptores Citoplasmáticos y Nucleares/química , Relación Estructura-Actividad , Factores de Transcripción/químicaRESUMEN
Synthesis and structure-activity relationships of tricyclic alpha-ethoxy-phenylpropionic acid derivatives guided by in vitro PPARalpha and PPARgamma transactivation data and computer modeling led to the identification of the novel carbazole analogue, 3q, with dual PPARalpha (EC(50) = 0.36 microM) and PPARgamma (EC(50) = 0.17 microM) activity in vitro. Ten days treatment of db/db mice with 3q improved the insulin sensitivity, as measured by OGTT, better than that seen with both pioglitazone and rosiglitazone treatment, suggesting in vivo PPARgamma activity. Likewise, 3q lowered plasma triglycerides and cholesterol in high cholesterol fed rats after 4 days treatment, indicating in vivo PPARalpha activity. Investigations of the pharmacokinetics of selected compounds suggested that extended drug exposure improved the in vivo activity of in vitro active compounds.
Asunto(s)
Carbazoles/síntesis química , Hipoglucemiantes/síntesis química , Hipolipemiantes/síntesis química , Proteínas Nucleares/agonistas , Fenilpropionatos/síntesis química , Receptores Citoplasmáticos y Nucleares/agonistas , Tiazolidinedionas , Factores de Transcripción/agonistas , Animales , Glucemia/metabolismo , Carbazoles/química , Carbazoles/farmacocinética , Carbazoles/farmacología , Colesterol/sangre , Colesterol en la Dieta/administración & dosificación , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Prueba de Tolerancia a la Glucosa , Hipoglucemiantes/química , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Hipolipemiantes/química , Hipolipemiantes/farmacocinética , Hipolipemiantes/farmacología , Masculino , Ratones , Modelos Moleculares , Fenilpropionatos/química , Fenilpropionatos/farmacocinética , Fenilpropionatos/farmacología , Pioglitazona , Ratas , Ratas Sprague-Dawley , Rosiglitazona , Estereoisomerismo , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/farmacocinética , Tiazoles/farmacología , Triglicéridos/sangreRESUMEN
The effects in the brain of selective estrogen receptor modulators (SERMs) such as tamoxifen and raloxifene have not yet been fully elucidated. Based upon the hypothesis that serotonin (5-HT)-steroid hormone interactions are important in mood regulation, we have compared six SERMs (tamoxifen, raloxifene, levormeloxifene, NNC 45-0781, NNC 45-0320, NNC 45-1506) with 17beta-estradiol (E(2)) in terms of their ability to regulate mRNA levels of estrogen receptor (ER)alpha, ER beta, 5-HT(1A) receptor, and 5-HT reuptake transporter (SERT) in the midbrain, amygdala, and hypothalamus of ovariectomized (OVX) rats. Female rats (n = 6/group, 8 groups total) were OVX and allowed to recover for 2 weeks. During the third post-OVX week, rats were injected subcutaneously with E(2) (0.1 mg/kg) or one of the SERMs (5 mg/kg) once per day for 7 days. Twenty-four hours after the last injection, tissue was collected for the determination of mRNA levels by ribonuclease protection assay (RPA). E(2) treatment significantly decreased mRNA levels for ER alpha, ER beta, and SERT in midbrain and ER alpha in hypothalamus. Tamoxifen increased ER beta mRNA levels in hypothalamus, while raloxifene increased ER beta mRNA levels in amygdala. NNC 45-0320 decreased ER alpha mRNA in hypothalamus and decreased ER beta mRNA in amygdala. These results suggest that while SERMs are not full estrogen receptor agonists in the brain, the agonist/antagonist profiles for individual SERMs may differ among brain areas. This raises the possibility of developing new SERMs for selective functions in specific brain areas.
Asunto(s)
Encéfalo/fisiología , Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso , Receptores de Estrógenos/genética , Serotonina/fisiología , Amígdala del Cerebelo/fisiología , Animales , Peso Corporal , Proteínas Portadoras/genética , Estradiol/química , Estradiol/farmacología , Antagonistas de Estrógenos/química , Antagonistas de Estrógenos/farmacología , Receptor alfa de Estrógeno , Receptor beta de Estrógeno , Femenino , Expresión Génica/efectos de los fármacos , Expresión Génica/fisiología , Hipotálamo/fisiología , Glicoproteínas de Membrana/genética , Mesencéfalo/fisiología , Ovariectomía , Pirrolidinas/química , Pirrolidinas/farmacología , ARN Mensajero/análisis , Clorhidrato de Raloxifeno/química , Clorhidrato de Raloxifeno/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Serotonina/genética , Receptores de Serotonina 5-HT1 , Proteínas de Transporte de Serotonina en la Membrana Plasmática , Tamoxifeno/química , Tamoxifeno/farmacologíaRESUMEN
Synthesis of (+/-)-cis-7-hydroxy-3-phenyl-4-(4-(2-piperidinoethanethio)phenyl)chromane (13) and (+/-)-cis-7-hydroxy-3-phenyl-4-(4-(2-pyrrolidinoethanethio)phenyl)chromane (15) is presented. These compounds are representatives of a novel class of compounds with high in vitro binding affinity for the estrogen receptor (IC(50)=7-10 nM), and very low in vitro uterotrophic activity (max stim.=5-17% rel to moxestrol; EC(50)=0.5-1.8 nM).
Asunto(s)
Cromanos/síntesis química , Receptores de Estrógenos/agonistas , Animales , Unión Competitiva , Cromanos/química , Cromanos/farmacología , Evaluación Preclínica de Medicamentos , Endometrio/citología , Endometrio/efectos de los fármacos , Estradiol/metabolismo , Femenino , Conejos , Relación Estructura-Actividad , Compuestos de Azufre/síntesis química , Compuestos de Azufre/química , Compuestos de Azufre/farmacologíaRESUMEN
The syntheses and in vitro pharmacological evaluation of a number of cis-3,4-diaryl-hydroxy-chromanes are reported, along with the results of a thorough in vivo profiling of the tissue-selective estrogen partial-agonist NNC 45-0781 [3, (-)-(3S,4R)-7-hydroxy-3-phenyl-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane]. These studies showed that NNC 45-0781 is a very promising candidate for the prevention of post-menopausal osteoporosis, and the treatment of other health issues related to the loss of endogenous estrogen production.