RESUMO
Models of atherosclerosis are used in preclinical studies but often fail to translate to humans. A model that better reflects human atherosclerosis is necessary. We recently engineered the ExeGen™ low-density lipoprotein receptor (LDLR) miniswine, in which the LDL receptor gene is modified to drive hypercholesterolemia and atherosclerosis, and showed diet-related exacerbation of these phenotypes. Five groups of animals, either wild type (+/+) or heterozygous (+/-), were fed either a normal or high-fat diet for 6 months. One group of heterozygous pigs fed a high-fat diet was also administered atorvastatin at 3 mg/kg/day. Clinical chemistry and anatomic pathology parameters were measured biweekly and at termination. The high-fat diet resulted in increased adiposity and interspersion of adipocytes within the salivary glands. The heterozygous pigs on the high-fat diet gained more weight and had significant increases in total cholesterol, high-density lipoprotein, and LDL compared to wild-type animals or heterozygous animals fed a normal diet. Atorvastatin attenuated these parameters, indicating the statin had a beneficial effect, even in a high-fat diet scenario. Atorvastatin treatment also reduced the intensity of Oil Red O staining in pigs on high-fat diet. Atorvastatin-related amelioration of several indices of cardiovascular pathophysiology in this model underscores its utility for drug discovery.
Assuntos
Modelos Animais de Doenças , Inibidores de Hidroximetilglutaril-CoA Redutases , Hipercolesterolemia , Receptores de LDL/genética , Pesquisa Translacional Biomédica/métodos , Animais , Animais Geneticamente Modificados , Aorta/efeitos dos fármacos , Aorta/patologia , Aterosclerose , Atorvastatina/farmacologia , Atorvastatina/uso terapêutico , Dieta Hiperlipídica , Artéria Femoral/efeitos dos fármacos , Artéria Femoral/patologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/metabolismo , Hipercolesterolemia/patologia , Suínos , Porco MiniaturaRESUMO
Development of effective vaccines against emerging infectious diseases (EID) can take as much or more than a decade to progress from pathogen isolation/identification to clinical approval. As a result, conventional approaches fail to produce field-ready vaccines before the EID has spread extensively. Lassa is a prototypical emerging infectious disease endemic to West Africa for which no successful vaccine is available. We established the VaxCelerate Consortium to address the need for more rapid vaccine development by creating a platform capable of generating and pre-clinically testing a new vaccine against specific pathogen targets in less than 120 d A self-assembling vaccine is at the core of the approach. It consists of a fusion protein composed of the immunostimulatory Mycobacterium tuberculosis heat shock protein 70 (MtbHSP70) and the biotin binding protein, avidin. Mixing the resulting protein (MAV) with biotinylated pathogen-specific immunogenic peptides yields a self-assembled vaccine (SAV). To meet the time constraint imposed on this project, we used a distributed R&D model involving experts in the fields of protein engineering and production, bioinformatics, peptide synthesis/design and GMP/GLP manufacturing and testing standards. SAV immunogenicity was first tested using H1N1 influenza specific peptides and the entire VaxCelerate process was then tested in a mock live-fire exercise targeting Lassa fever virus. We demonstrated that the Lassa fever vaccine induced significantly increased class II peptide specific interferon-γ CD4(+) T cell responses in HLA-DR3 transgenic mice compared to peptide or MAV alone controls. We thereby demonstrated that our SAV in combination with a distributed development model may facilitate accelerated regulatory review by using an identical design for each vaccine and by applying safety and efficacy assessment tools that are more relevant to human vaccine responses than current animal models.
Assuntos
Avidina/imunologia , Proteínas de Bactérias/imunologia , Proteínas de Choque Térmico HSP70/imunologia , Febre Lassa/imunologia , Febre Lassa/prevenção & controle , Vacinas Virais/imunologia , Animais , Avidina/uso terapêutico , Proteínas de Bactérias/uso terapêutico , Linfócitos T CD4-Positivos/imunologia , Doenças Transmissíveis Emergentes/prevenção & controle , Feminino , Antígeno HLA-DR3/genética , Proteínas de Choque Térmico HSP70/uso terapêutico , Vírus da Influenza A Subtipo H1N1/imunologia , Interferon gama/imunologia , Vírus Lassa/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mycobacterium tuberculosis/imunologia , Ovalbumina/imunologia , Engenharia de Proteínas , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/uso terapêutico , Vacinas Virais/uso terapêuticoRESUMO
Continuing studies based on dihydroquinoline glucocorticoid receptor agonists lead to the discovery of a series of C4-oxime analogs. Representative compounds exhibited potent transrepression activity with minimal transactivation of phosphoenolpyruvate caboxykinase (PEPCK), a key protein in the gluconeogenesis pathway. These compounds represent promising leads in identifying GR agonists with high anti-inflammatory activity and attenuated potential for glucose elevation.
Assuntos
Carboxiliases/metabolismo , Quinolinas/farmacologia , Receptores de Glucocorticoides/agonistas , Ativação Enzimática , Quinolinas/química , Relação Estrutura-AtividadeRESUMO
Continuing studies on tetrahydroquinoline glucocorticoid receptor anti-inflammatory agents lead to the identification of several tetrahydroquinolin-3-yl carbamates that exhibited steroid-like activity in in vitro transrepression assays with reduced transactivation of phosphoenol pyruvate carboxykinase (PEPCK), a key enzyme in the gluconeogenesis pathway.
Assuntos
Carboxiliases/metabolismo , Quinolinas/farmacologia , Receptores de Glucocorticoides/agonistas , Ativação EnzimáticaRESUMO
A series of tetrahydroquinoline derivatives were synthesized and profiled for their ability to act as glucocorticoid receptor selective modulators. Structure-activity relationships of the tetrahydroquinoline B-ring lead to the discovery of orally available GR-selective agonists with high in vivo activity.
Assuntos
Quinolinas/farmacologia , Receptores de Glucocorticoides/agonistas , Administração Oral , Animais , Descoberta de Drogas , Ensaio de Imunoadsorção Enzimática , Humanos , Quinolinas/administração & dosagem , Quinolinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
We have previously disclosed a series of glucocorticoid receptor (GR) ligands derived from 6-indole-1,2,3,4-tetrahydroquinolines through structure-activity relationship (SAR) of the pendent C6-indole ring. In parallel with this effort, we now report SAR of the tetrahydroquinoline A-ring that identified the importance of a C3 hydroxyl in improving GR selectivity within a series of non-steroidal GR agonists.
Assuntos
Quinolinas/química , Receptores de Glucocorticoides/agonistas , Avaliação Pré-Clínica de Medicamentos , Ligação Proteica , Quinolinas/síntese química , Quinolinas/farmacologia , Receptores de Glucocorticoides/metabolismo , Relação Estrutura-AtividadeRESUMO
Throughout the centuries, traditional Chinese medicine has been a rich resource in the development of new drugs. Modern drug discovery, which relies increasingly on automated high throughput screening and quick hit-to-lead development, however, is confronted with the challenges of the chemical complexity associated with natural products. New technologies for biological screening as well as library building are in great demand in order to meet the requirements. Here we review the developments in these techniques under the perspective of their applicability in natural product drug discovery. Methods in library building, component characterizing, biological evaluation, and other screening methods including NMR and X-ray diffraction are discussed.
Assuntos
Produtos Biológicos/química , Produtos Biológicos/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Ensaios de Triagem em Larga Escala/métodos , Medicina Tradicional Chinesa , Animais , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Plantas Medicinais/químicaRESUMO
Selective antagonists of the glucocorticoid receptor (GR) are desirable for the treatment of hypercortisolemia associated with Cushing's syndrome, psychic depression, obesity, diabetes, neurodegenerative diseases, and glaucoma. NC3327, a non-steroidal small molecule with potent binding affinity to GR (K(i)=13.2nM), was identified in a high-throughput screening effort. As a full GR antagonist, NC3327 greatly inhibits the dexamethasone (Dex) induction of marker genes involved in hepatic gluconeogenesis, but has a minimal effect on matrix metalloproteinase 9 (MMP-9), a GR responsive pro-inflammatory gene. Interestingly, the compound recruits neither coactivators nor corepressors to the GR complex but competes with glucocorticoids for the interaction between GR and a coactivator peptide. Moreover, NC3327 does not trigger GR nuclear translocation, but significantly blocks Dex-induced GR transportation to the nucleus, and thus appears to be a 'competitive' GR antagonist. Therefore, the non-steroidal compound, NC3327, may represent a new class of GR antagonists as potential therapeutics for a variety of cortisol-related endocrine disorders.
Assuntos
Gluconeogênese/efeitos dos fármacos , Indóis/farmacologia , Fígado/efeitos dos fármacos , Receptores de Glucocorticoides/antagonistas & inibidores , Xantenos/farmacologia , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Linhagem Celular , Núcleo Celular/metabolismo , Dexametasona/antagonistas & inibidores , Dexametasona/farmacologia , Expressão Gênica/efeitos dos fármacos , Gluconeogênese/genética , Humanos , Indóis/química , Fígado/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Receptores de Glucocorticoides/metabolismo , Xantenos/químicaRESUMO
Recent clinical trials with bisphosphonates and PTH have not supported the hypothesis that combination treatments with antiresorptive and anabolic agents would lead to synergistic activity. We hypothesized that combination treatment with a selective androgen receptor modulator (SARM), LGD-3303, and a bisphosphonate would be beneficial. In vitro competitive binding and transcriptional activity assays were used to characterize LGD-3303. LGD-3303 is a potent nonsteroidal androgen that shows little or no cross-reactivity with related nuclear receptors. Tissue selective activity of LGD-3303 was assessed in orchidectomized male rats orally administered LGD-3303 for 14 days. LGD-3303 increased the levator ani muscle weight above eugonadal levels but had greatly reduced activity on the prostate, never increasing the ventral prostate weight to >50% of eugonadal levels even at high doses. Ovariectomized female rats were treated with LGD-3303, alendronate, or combination treatment to study the effects on bone. DXA scans, histomorphometry, and biomechanics were performed. LGD-3303 increased muscle weight in females rats. In addition, LGD-3303 increased BMD and BMC at both cortical and cancellous bone sites. At cortical sites, the effects were caused in part by anabolic activity on the periosteal surface. At every measured site, combination treatment was as effective as either single agent and in some cases showed significant added benefit. LGD-3303 is a novel SARM with anabolic effects on muscle and cortical bone not observed with bisphosphonates. Combination therapy with LGD-3303 and alendronate had additive effects and may potentially be a useful therapy for osteoporosis and frailty.
Assuntos
Antagonistas de Androgênios/uso terapêutico , Doenças Ósseas Metabólicas/tratamento farmacológico , Difosfonatos/uso terapêutico , Absorciometria de Fóton , Antagonistas de Androgênios/farmacologia , Animais , Fenômenos Biomecânicos/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Doenças Ósseas Metabólicas/sangue , Doenças Ósseas Metabólicas/fisiopatologia , Difosfonatos/farmacologia , Sinergismo Farmacológico , Quimioterapia Combinada , Estrogênios/deficiência , Feminino , Fêmur/efeitos dos fármacos , Fêmur/patologia , Fêmur/fisiopatologia , Vértebras Lombares/efeitos dos fármacos , Vértebras Lombares/patologia , Vértebras Lombares/fisiopatologia , Masculino , Orquiectomia , Tamanho do Órgão/efeitos dos fármacos , Osteocalcina/sangue , Ovariectomia , Pirróis/farmacologia , Pirróis/uso terapêutico , Quinolonas/farmacologia , Quinolonas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Transcrição Gênica/efeitos dos fármacosRESUMO
A series of nonsteroidal glucocorticoid receptor (GR) ligands based on a 6-indole-1,2,3,4-tetrahydroquinoline scaffold are reported. Structure-activity relationship (SAR) of the pendent indole group identified compound 20 exhibiting good GR binding affinity (K(i)=1.5nM) and 100- to 1000-fold selectivity over MR, PR, and AR while showing activity in an E-selectin repression assay.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Indóis/farmacologia , Quinolinas/farmacologia , Receptores de Glucocorticoides/efeitos dos fármacos , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Sítios de Ligação , Avaliação Pré-Clínica de Medicamentos , Indóis/síntese química , Indóis/química , Ligantes , Estrutura Molecular , Quinolinas/síntese química , Quinolinas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The progesterone receptor plays an important role in the female reproductive system. Here we describe the discovery of a new selective progesterone receptor modulator (SPRM). In rats, the lead compound, 7,9-difluoro-5-(3-methylcyclohex-2-enyl)-2,2,4-trimethyl-1,2-dihydrochromeno[3,4- f]quinoline ( 5c), inhibited ovulation and showed full efficacy in uterine and vaginal tissue but was a mixed partial agonist/antagonist in breast tissue. The compound also suppressed ovulation in monkeys, but in contrast to currently approved steroidal PR agonists, it did not suppress estradiol levels.
Assuntos
Benzopiranos/síntese química , Benzopiranos/farmacologia , Quinolinas/síntese química , Quinolinas/farmacologia , Receptores de Progesterona/antagonistas & inibidores , Animais , Benzopiranos/química , Feminino , Haplorrinos , Humanos , Estrutura Molecular , Ovulação/efeitos dos fármacos , Quinolinas/química , Ratos , Receptores de Progesterona/metabolismo , Relação Estrutura-AtividadeRESUMO
Glucocorticoids are commonly used antiinflammatory agents whose use is limited by side effects. We have developed a series of glucocorticoid receptor (GR) ligands that retain the strong antiinflammatory activity of conventional glucocorticoids with reduced side effects. We present a compound, LGD5552, that binds the receptor efficiently and strongly represses inflammatory gene expression. LGD5552 bound to GR activates gene expression somewhat differently than glucocorticoids. It activates some genes with an efficacy similar to that of the glucocorticoids. However, other glucocorticoid-activated genes are not regulated by LGD5552. These differences may be because of the more efficient binding of corepressor in the presence of LGD5552, compared with glucocorticoid agonists. This class of nonsteroidal, GR-dependent antiinflammatory drugs may offer a safer alternative to steroidal glucocorticoids in the treatment of inflammatory disease.
Assuntos
Anti-Inflamatórios/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Benzopiranos/farmacologia , Compostos de Benzilideno/farmacologia , Glucocorticoides/farmacologia , Receptores de Glucocorticoides/antagonistas & inibidores , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Benzopiranos/química , Benzopiranos/uso terapêutico , Compostos de Benzilideno/química , Compostos de Benzilideno/uso terapêutico , Linhagem Celular Tumoral , Expressão Gênica/efeitos dos fármacos , Glucocorticoides/química , Glucocorticoides/uso terapêutico , Ligantes , Camundongos , Camundongos Endogâmicos , Osteogênese/efeitos dos fármacos , Ratos , Receptores de Glucocorticoides/metabolismoRESUMO
Structure-activity relationship studies centered around 3'-substituted (Z)-5-(2'-(thienylmethylidene))1,2-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5H-chromeno[3,4-f]quinolines are described. A series of highly potent and efficacious selective glucocorticoid receptor modulators were identified with in vitro activity comparable to dexamethasone. In vivo evaluation of these compounds utilizing a 28 day mouse tumor xenograft model demonstrated efficacy equal to dexamethasone in the reduction of tumor volume.
Assuntos
Antineoplásicos/síntese química , Benzopiranos/síntese química , Mieloma Múltiplo/tratamento farmacológico , Quinolinas/síntese química , Receptores de Glucocorticoides/efeitos dos fármacos , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzopiranos/química , Benzopiranos/farmacologia , Ligação Competitiva , Dexametasona/farmacologia , Humanos , Camundongos , Antagonistas de Receptores de Mineralocorticoides , Modelos Moleculares , Mieloma Múltiplo/patologia , Quinolinas/química , Quinolinas/farmacologia , Receptores de Glucocorticoides/agonistas , Receptores de Glucocorticoides/antagonistas & inibidores , Receptores de Mineralocorticoides/agonistas , Estereoisomerismo , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Recent interest in orally available androgens has fueled the search for new androgens for use in hormone replacement therapy and as anabolic agents. In pursuit of this, we have discovered a series of novel androgen receptor modulators derived from 7H-[1,4]oxazino[3,2-g]quinolin-7-ones. These compounds were synthesized and evaluated in competitive binding assays and an androgen receptor transcriptional activation assay. A number of compounds from the series demonstrated single-digit nanomolar agonist activity in vitro. In addition, lead compound (R)-16e was orally active in established rodent models that measure androgenic and anabolic properties of these agents. In this assay, (R)-16e demonstrated full efficacy in muscle and only partially stimulated the prostate at 100 mg/kg. These data suggest that these compounds may be utilized as selective androgen receptor modulators or SARMs. This series represents a novel class of compounds for use in androgen replacement therapy.
Assuntos
Oxazinas/síntese química , Quinolonas/síntese química , Receptores Androgênicos/efeitos dos fármacos , Anabolizantes/síntese química , Anabolizantes/química , Anabolizantes/farmacologia , Androgênios , Animais , Ligação Competitiva , Linhagem Celular Tumoral , Humanos , Masculino , Músculo Esquelético/anatomia & histologia , Músculo Esquelético/efeitos dos fármacos , Tamanho do Órgão/efeitos dos fármacos , Oxazinas/química , Oxazinas/farmacologia , Próstata/anatomia & histologia , Próstata/efeitos dos fármacos , Quinolonas/química , Quinolonas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Ativação Transcricional/efeitos dos fármacosRESUMO
Specific retinoid X receptor (RXR) agonists, such as LG100268 (LG268), and the thiazolidinedione (TZD) PPARgamma agonists, such as rosiglitazone, produce insulin sensitization in rodent models of insulin resistance and type 2 diabetes. In sharp contrast to the TZDs that produce significant increases in body weight gain, RXR agonists reduce body weight gain and food consumption. Unfortunately, RXR agonists also suppress the thyroid hormone axis and generally produce hypertriglyceridemia. Heterodimer-selective RXR modulators have been identified that, in rodents, retain the metabolic benefits of RXR agonists with reduced side effects. These modulators bind specifically to RXR with high affinity and are RXR homodimer partial agonists. Although RXR agonists activate many heterodimer partners, these modulators selectively activate RXR:PPARalpha and RXR:PPARgamma, but not RXR:RARalpha, RXR:LXRalpha, RXR:LXRbeta, or RXR:FXRalpha. We report the in vivo characterization of one RXR modulator, LG101506 (LG1506). In Zucker fatty (fa/fa) rats, LG1506 is a potent insulin sensitizer that also enhances the insulin-sensitizing activities of rosiglitazone. Administration of LG1506 reduces both body weight gain and food consumption and blocks the TZD-induced weight gain when coadministered with rosiglitazone. LG1506 does not significantly suppress the thyroid hormone axis in rats, nor does it elevate triglycerides in Sprague Dawley rats. However, LG1506 produces a unique pattern of triglycerides elevation in Zucker rats. LG1506 elevates high-density lipoprotein cholesterol in humanized apolipoprotein A-1-transgenic mice. Therefore, selective RXR modulators are a promising approach for developing improved therapies for type 2 diabetes, although additional studies are needed to understand the strain-specific effects on triglycerides.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Ácidos Graxos Insaturados/administração & dosagem , Hipoglicemiantes/administração & dosagem , Obesidade/tratamento farmacológico , Éteres Fenílicos/administração & dosagem , Receptores X de Retinoides/agonistas , Tiazolidinedionas/administração & dosagem , Análise de Variância , Animais , Apolipoproteína A-I/genética , Apolipoproteína A-I/fisiologia , Área Sob a Curva , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Hipoglicemiantes/uso terapêutico , Camundongos , Camundongos Transgênicos , Obesidade/sangue , Obesidade/complicações , PPAR gama/agonistas , PPAR gama/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Zucker , Receptores X de Retinoides/metabolismo , Rosiglitazona , Estatísticas não Paramétricas , Tiazolidinedionas/farmacologia , Tiazolidinedionas/uso terapêutico , Glândula Tireoide/efeitos dos fármacos , Triglicerídeos/sangueRESUMO
To understand the species selectivity in a series of alpha-methyl-alpha-phenoxy carboxylic acid PPARalpha/gamma dual agonists (1-11), structure-based molecular modeling was carried out in the ligand binding pockets of both human and mouse PPARalpha. This study suggested that interaction of both 4-phenoxy and phenyloxazole substituents of these ligands with F272 and M279 in mouse PPARalpha leads to the species-specific divergence in ligand binding. Insights obtained in the molecular modeling studies of these key interactions resulted in the ability to convert a human-selective PPARalpha agonist to a human and mouse dual agonist within the same platform.
Assuntos
Cinamatos/síntese química , Modelos Moleculares , PPAR alfa/agonistas , Animais , Cinamatos/química , Cinamatos/farmacologia , Desenho de Fármacos , Humanos , Ligantes , Camundongos , Estrutura Molecular , Especificidade da Espécie , Relação Estrutura-AtividadeRESUMO
The design and synthesis of the dual peroxisome proliferator activated receptor (PPAR) alpha/gamma agonist (S)-2-methyl-3-[4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)ethoxy]phenyl]-2-phenoxypropionic acid (2) for the treatment of type 2 diabetes and associated dyslipidemia are described. 2 possesses a potent dual hPPAR alpha/gamma agonist profile (IC(50) = 28 and 10 nM; EC(50) = 9 and 4 nM, respectively, for hPPARalpha and hPPARgamma). In preclinical models, 2 substantially improves insulin sensitivity and potently reverses diabetic hyperglycemia while significantly improving overall lipid homeostasis.
Assuntos
Hipoglicemiantes/síntese química , Hipolipemiantes/síntese química , Fenilpropionatos/síntese química , Receptores Citoplasmáticos e Nucleares/agonistas , Tiofenos/síntese química , Fatores de Transcrição/agonistas , Animais , Ligação Competitiva , Linhagem Celular , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Humanos , Hiperlipidemias/tratamento farmacológico , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Fenilpropionatos/química , Fenilpropionatos/farmacologia , Ensaio Radioligante , Ratos , Ratos Zucker , Estereoisomerismo , Relação Estrutura-Atividade , Tiofenos/química , Tiofenos/farmacologiaRESUMO
A series of 5-benylidene-1,2-dihydrochromeno[3,4-f]quinolines (4) were synthesized and tested in bioassays to evaluate their progestational activities, receptor- and tissue-selectivity profiles as selective progesterone receptor modulators (SPRMs). Most of the new analogues exhibited as highly potent progestins with more than 100-fold receptor selectivity over other steroid hormone receptors and LG120920 (7b) demonstrated tissue selectivity toward uterus and vagina versus breasts in a rodent model after oral administration.
Assuntos
Compostos de Benzilideno/química , Compostos de Benzilideno/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Receptores de Progesterona/antagonistas & inibidores , Antagonistas de Receptores de Andrógenos , Animais , Compostos de Benzilideno/metabolismo , Ligação Competitiva , Neoplasias da Mama/metabolismo , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Chlorocebus aethiops , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Estrona/antagonistas & inibidores , Estrona/farmacologia , Feminino , Humanos , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Animais/efeitos dos fármacos , Acetato de Medroxiprogesterona/metabolismo , Acetato de Medroxiprogesterona/farmacologia , Progesterona/metabolismo , Progesterona/farmacologia , Congêneres da Progesterona/química , Congêneres da Progesterona/metabolismo , Congêneres da Progesterona/farmacologia , Quinolinas/síntese química , Ratos , Receptores Androgênicos/metabolismo , Receptores de Glucocorticoides/antagonistas & inibidores , Receptores de Glucocorticoides/metabolismo , Receptores de Progesterona/metabolismo , Relação Estrutura-Atividade , Útero/citologia , Útero/efeitos dos fármacos , Vagina/citologia , Vagina/efeitos dos fármacosRESUMO
A series of 5-methylidene 1,2-dihydrochromeno[3,4-f]quinoline derivatives were synthesized and tested in biological assays to evaluate scope and limitations of the nonsteroidal SPRM pharmacophore (3). A number of orally available highly potent nonsteroidal modulators were identified by modification of the substituents at 5-methylidene position.
Assuntos
Quinolinas/síntese química , Quinolinas/farmacologia , Receptores de Progesterona/agonistas , Receptores de Progesterona/antagonistas & inibidores , Administração Oral , Animais , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Chlorocebus aethiops , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Estradiol/farmacologia , Feminino , Humanos , Concentração Inibidora 50 , Progesterona/farmacologia , Quinolinas/química , Ratos , Receptores de Progesterona/metabolismo , Receptores de Esteroides/antagonistas & inibidores , Relação Estrutura-Atividade , Transcrição Gênica/efeitos dos fármacos , Transfecção , Útero/citologia , Útero/efeitos dos fármacosRESUMO
A series of 1,2-dihydrochromeno[3,4-f]quinoline derivatives was synthesized and tested in biological assays to evaluate the nonsteroidal progesterone receptor modulator pharmacophore (4) as antiprogestins. A number of potent analogues were identified by modification of the substituents at the D-ring.