RESUMO
A series of quinoline-3-carboxamide containing sulfones was prepared and found to have good binding affinity for LXRbeta and moderate binding selectivity over LXRalpha. The 8-Cl quinoline analog 33 with a high TPSA score, displayed 34-fold binding selectivity for LXRbeta over LXRalpha (LXRbeta IC(50)=16nM), good activity for inducing ABCA1 gene expression in a THP macrophage cell line, desired weak potency in the LXRalpha Gal4 functional assay, and low blood-brain barrier penetration in rat.
Assuntos
Barreira Hematoencefálica/metabolismo , Receptores Nucleares Órfãos/agonistas , Quinolinas/química , Sulfonas/química , Transportador 1 de Cassete de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Sítios de Ligação , Linhagem Celular , Simulação por Computador , Humanos , Ligação de Hidrogênio , Receptores X do Fígado , Receptores Nucleares Órfãos/metabolismo , Ligação Proteica , Quinolinas/síntese química , Quinolinas/farmacocinética , Ratos , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/farmacocinéticaRESUMO
A series of cinnolines/quinolines was prepared and it was found that 4-phenyl-cinnoline/quinolines with either a 2',3' or 2',5'-disubstituted benzyloxy moiety or the 1-Me-7-indole methoxy moiety on the meta position of the 4-phenyl ring showed good binding selectivity for LXRbeta over LXRalpha. The LXRbeta binding selective modulators displayed good activity for inducing ABCA1 gene expression in J774 macrophage cell line and poor efficacy in the LXRalpha Gal4 functional assay. 26, 37 and 41 were examined for their ability to induce SREBP-1c gene expression in Huh-7 liver cell line and they were weak partial agonists.
Assuntos
Proteínas de Ligação a DNA/agonistas , Compostos Heterocíclicos com 2 Anéis/química , Quinolinas/química , Receptores Citoplasmáticos e Nucleares/agonistas , Transportador 1 de Cassete de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Linhagem Celular , Simulação por Computador , Proteínas de Ligação a DNA/metabolismo , Descoberta de Drogas , Humanos , Receptores X do Fígado , Camundongos , Receptores Nucleares Órfãos , Quinolinas/síntese química , Quinolinas/farmacologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Relação Estrutura-AtividadeRESUMO
A structure-based approach was used to optimize our new class of quinoline LXR modulators leading to phenyl acetic acid substituted quinolines 15 and 16. Both compounds displayed good binding affinity for LXRbeta and LXRalpha and were potent activators in LBD transactivation assays. The compounds also increased expression of ABCA1 and stimulated cholesterol efflux in THP-1 cells. Quinoline 16 showed good oral bioavailability and in vivo efficacy in a LDLr knockout mouse model for lesions.
Assuntos
Anticolesterolemiantes/síntese química , Aterosclerose/tratamento farmacológico , Proteínas de Ligação a DNA/agonistas , Fenilacetatos/síntese química , Quinolinas/síntese química , Receptores Citoplasmáticos e Nucleares/agonistas , Transportador 1 de Cassete de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/biossíntese , Animais , Anticolesterolemiantes/química , Anticolesterolemiantes/farmacologia , Sítios de Ligação , Disponibilidade Biológica , Linhagem Celular , Colesterol/metabolismo , Proteínas de Ligação a DNA/genética , Estabilidade de Medicamentos , Feminino , Humanos , Técnicas In Vitro , Ligantes , Receptores X do Fígado , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Receptores Nucleares Órfãos , Fenilacetatos/química , Fenilacetatos/farmacologia , Estrutura Terciária de Proteína , Quinolinas/química , Quinolinas/farmacologia , Receptores Citoplasmáticos e Nucleares/genética , Relação Estrutura-Atividade , Ativação TranscricionalRESUMO
New diphenolic azoles as highly selective estrogen receptor-beta agonists are reported. The more potent and selective analogues of these series have comparable binding affinities for ERbeta as the natural ligand 17beta-estradiol but are >100-fold selective over ERalpha. Our design strategy not only followed a traditional SAR approach but also was supported by X-ray structures of ERbeta cocrystallized with various ligands as well as molecular modeling studies. These strategies enabled us to take advantage of a single conservative residue substitution in the ligand-binding pocket, ERalpha Met(421) --> ERbeta Ile(373), to optimize ERbeta selectivity. The 7-position-substituted benzoxazoles (Table 5) were the most selective ligands of both azole series, with ERB-041 (117) being >200-fold selective for ERbeta. The majority of ERbeta selective agonists tested that were at least approximately 50-fold selective displayed a consistent in vivo profile: they were inactive in several models of classic estrogen action (uterotrophic, osteopenia, and vasomotor instability models) and yet were active in the HLA-B27 transgenic rat model of inflammatory bowel disease. These data suggest that ERbeta-selective agonists are devoid of classic estrogenic effects and may offer a novel therapy to treat certain inflammatory conditions.
Assuntos
Isoxazóis/síntese química , Fenóis/síntese química , Receptores de Estrogênio/agonistas , Antagonistas de Androgênios/síntese química , Antagonistas de Androgênios/química , Antagonistas de Androgênios/farmacologia , Animais , Animais Geneticamente Modificados , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Sítios de Ligação , Temperatura Corporal/efeitos dos fármacos , Doenças Ósseas Metabólicas/prevenção & controle , Linhagem Celular Tumoral , Cristalografia por Raios X , Desenho de Fármacos , Receptor beta de Estrogênio , Feminino , Antígeno HLA-B27/genética , Humanos , Isoxazóis/química , Isoxazóis/farmacologia , Masculino , Camundongos , Modelos Moleculares , Tamanho do Órgão/efeitos dos fármacos , Fenóis/química , Fenóis/farmacologia , Próstata/anatomia & histologia , Próstata/efeitos dos fármacos , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores de Estrogênio/química , Relação Estrutura-Atividade , Transcrição Gênica/efeitos dos fármacos , Útero/anatomia & histologia , Útero/efeitos dos fármacosRESUMO
A series of 2-(4-hydroxy-phenyl)-benzofuran-5-ols with relatively lipophilic groups in the 7-position of the benzofuran was prepared and the affinity and selectivity for ER beta was measured. Many of the analogues were found to be potent and selective ER beta ligands. Additional modifications at the benzofuran 4-position as well as at the 3'-position of the 2-phenyl group were found to further increase selectivity. Such modifications led to compounds with <10 nM potency and >100-fold selectivity for ER beta.
Assuntos
Benzofuranos/síntese química , Receptor beta de Estrogênio/agonistas , Benzofuranos/metabolismo , Linhagem Celular Tumoral , Receptor beta de Estrogênio/química , Receptor beta de Estrogênio/metabolismo , Humanos , Proteína 4 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Ligantes , RNA Mensageiro/análise , Relação Estrutura-AtividadeRESUMO
A new series of ERbeta (ERbeta) selective ligands has been prepared. One of the compounds 6, structurally related to the phytoestrogen apigenin 4, displays a binding preference for ERbeta over ERalpha of over 40-fold. In addition to its binding selectivity, 6 was able to potently induce metallothionein (an ERbeta specific response in human SAOS-2 cells) while demonstrating low potency in an ERalpha dependant ERE-tk luciferase assay in MCF-7 cells. Such receptor and cell selectivity could make 6 a useful molecular probe for better understanding the role of ERbeta in mammalian physiology.
