RESUMO
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.
Assuntos
Alcenos/síntese química , Propionatos/síntese química , Receptores Citoplasmáticos e Nucleares/agonistas , Fatores de Transcrição/agonistas , Alcenos/farmacocinética , Alcenos/farmacologia , Sequência de Aminoácidos , Animais , Sítios de Ligação , Disponibilidade Biológica , Linhagem Celular , Cristalografia por Raios X , Dimerização , Humanos , Ligantes , Masculino , Camundongos , Modelos Moleculares , Dados de Sequência Molecular , Propionatos/farmacocinética , Propionatos/farmacologia , Ratos , Receptores Citoplasmáticos e Nucleares/química , Receptores Citoplasmáticos e Nucleares/metabolismo , Alinhamento de Sequência , Estereoisomerismo , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo , Ativação TranscricionalRESUMO
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.
Assuntos
Carbazóis/síntese química , Hipoglicemiantes/síntese química , Hipolipemiantes/síntese química , Proteínas Nucleares/agonistas , Fenilpropionatos/síntese química , Receptores Citoplasmáticos e Nucleares/agonistas , Tiazolidinedionas , Fatores de Transcrição/agonistas , Animais , Glicemia/metabolismo , Carbazóis/química , Carbazóis/farmacocinética , Carbazóis/farmacologia , Colesterol/sangue , Colesterol na Dieta/administração & dosagem , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Teste de Tolerância a Glucose , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Hipolipemiantes/química , Hipolipemiantes/farmacocinética , Hipolipemiantes/farmacologia , Masculino , Camundongos , Modelos Moleculares , Fenilpropionatos/química , Fenilpropionatos/farmacocinética , Fenilpropionatos/farmacologia , Pioglitazona , Ratos , Ratos Sprague-Dawley , Rosiglitazona , Estereoisomerismo , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacocinética , Tiazóis/farmacologia , Triglicerídeos/sangueRESUMO
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.
Assuntos
Desenho de Fármacos , PPAR alfa/agonistas , Fenilpropionatos/química , Fenilpropionatos/farmacologia , Animais , Computadores , Cristalografia , Ligantes , PPAR alfa/química , Fenilpropionatos/síntese químicaRESUMO
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.
Assuntos
Encéfalo/fisiologia , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso , Receptores de Estrogênio/genética , Serotonina/fisiologia , Tonsila do Cerebelo/fisiologia , Animais , Peso Corporal , Proteínas de Transporte/genética , Estradiol/química , Estradiol/farmacologia , Antagonistas de Estrogênios/química , Antagonistas de Estrogênios/farmacologia , Receptor alfa de Estrogênio , Receptor beta de Estrogênio , Feminino , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/fisiologia , Hipotálamo/fisiologia , Glicoproteínas de Membrana/genética , Mesencéfalo/fisiologia , Ovariectomia , Pirrolidinas/química , Pirrolidinas/farmacologia , RNA Mensageiro/análise , Cloridrato de Raloxifeno/química , Cloridrato de Raloxifeno/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Serotonina/genética , Receptores 5-HT1 de Serotonina , Proteínas da Membrana Plasmática de Transporte de Serotonina , Tamoxifeno/química , Tamoxifeno/farmacologiaRESUMO
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).
Assuntos
Cromanos/síntese química , Receptores de Estrogênio/agonistas , Animais , Ligação Competitiva , Cromanos/química , Cromanos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Endométrio/citologia , Endométrio/efeitos dos fármacos , Estradiol/metabolismo , Feminino , Coelhos , Relação Estrutura-Atividade , Compostos de Enxofre/síntese química , Compostos de Enxofre/química , Compostos de Enxofre/farmacologiaRESUMO
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.
Assuntos
Cromanos/síntese química , Cromanos/farmacologia , Receptores de Estrogênio/agonistas , Animais , Densidade Óssea , Colesterol/sangue , Cromanos/química , Avaliação Pré-Clínica de Medicamentos , Feminino , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo III , Tamanho do Órgão , Ratos , Ratos Sprague-Dawley , Vagina/citologiaRESUMO
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.