RESUMO
BACKGROUND & AIMS: Molecular mechanisms underlying the different susceptibility of men and women to non-alcoholic fatty liver disease (NAFLD) are poorly understood. The TTC39B locus encodes a scaffolding protein, associates with gynecological disorders and its deletion protects mice from diet-induced steatohepatitis. This study aimed to elucidate the molecular mechanisms linking TTC39B (T39) to the expression of lipogenic genes and to explore sex-specific effects. METHODS: Co-expression in HEK293A cells validated the novel T39/pRb interaction predicted by a protein-protein interaction algorithm. T39 was knocked down using an antisense oligonucleotide (ASO) in mice with dietary NAFLD and a genetic deficiency of pRb or its downstream effector E2F1, as well as in primary human hepatocytes. RESULTS: T39 interacts with pRb via its C-terminal TPR domain and promotes its proteasomal degradation. In female mice, T39 deficiency reduces the mRNA of lipogenic genes, especially Pnpla3, in a pRb- and E2F1-dependent manner. In contrast, in male mice, T39 deficiency results in a much smaller reduction in lipogenic gene expression that is independent of pRb/E2F1. T39 also interacts with VAPB via an N-terminal FFAT motif and stabilizes the interaction of VAPB with SCAP. Ovariectomy abolishes the effect of T39 knockdown on the hepatic pRb/E2F1/Pnpla3 axis. In both sexes T39 knockdown reduces SCAP independently of pRb. In primary human hepatocytes, T39 knockdown reduces expression of PNPLA3 and other lipogenic genes in women but not men. CONCLUSIONS: We have uncovered a conserved sexual dimorphism in the regulation of hepatic lipogenic genes, with effects of T39 mediated through pRb/E2F1 in females and VAPB/SCAP in both sexes. T39 inhibition could be a novel strategy to downregulate PNPLA3 and treat NAFLD in women. LAY SUMMARY: In females, the protein TTC39B degrades a tumor suppressor in the liver to promote the synthesis of new fat and the expression of a major genetic risk factor for non-alcoholic fatty liver disease. TTC39B is a potential therapeutic target for non-alcoholic fatty liver disease, especially in women.
Assuntos
Lipoproteínas HDL/efeitos adversos , Proteínas de Neoplasias/efeitos adversos , Proteína do Retinoblastoma/efeitos dos fármacos , Fatores Sexuais , Animais , Modelos Animais de Doenças , Expressão Gênica/genética , Expressão Gênica/fisiologia , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Camundongos , Camundongos Endogâmicos C57BL/metabolismoRESUMO
RATIONALE: Macrophages face a substantial amount of cholesterol after the ingestion of apoptotic cells, and the LIPA (lysosomal acid lipase) has a major role in hydrolyzing cholesteryl esters in the endocytic compartment. OBJECTIVE: Here, we directly investigated the role of LIPA-mediated clearance of apoptotic cells both in vitro and in vivo. METHODS AND RESULTS: We show that LIPA inhibition causes a defective efferocytic response because of impaired generation of 25-hydroxycholesterol and 27-hydroxycholesterol. Reduced synthesis of 25-hydroxycholesterol after LIPA inhibition contributed to defective mitochondria-associated membrane leading to mitochondrial oxidative stress-induced NLRP3 (NOD-like receptor family, pyrin domain containing) inflammasome activation and caspase-1-dependent Rac1 (Ras-related C3 botulinum toxin substrate 1) degradation. A secondary event consisting of failure to appropriately activate liver X receptor-mediated pathways led to mitigation of cholesterol efflux and apoptotic cell clearance. In mice, LIPA inhibition caused defective clearance of apoptotic lymphocytes and stressed erythrocytes by hepatic and splenic macrophages, culminating in splenomegaly and splenic iron accumulation under hypercholesterolemia. CONCLUSIONS: Our findings position lysosomal cholesterol hydrolysis as a critical process that prevents metabolic inflammation by enabling efficient macrophage apoptotic cell clearance.
Assuntos
Colesterol/metabolismo , Inflamação/metabolismo , Lisossomos/metabolismo , Macrófagos/metabolismo , Oxisteróis/metabolismo , Esterol Esterase/metabolismo , Animais , Apoptose , Transporte Biológico , Ésteres do Colesterol/metabolismo , Eritrócitos/metabolismo , Hidrólise , Hipercolesterolemia/metabolismo , Inflamassomos/metabolismo , Receptores X do Fígado/metabolismo , Linfócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neuropeptídeos/metabolismo , Receptores de LDL/metabolismo , Esplenomegalia/metabolismo , Esterol Esterase/antagonistas & inibidores , Proteínas rac1 de Ligação ao GTP/metabolismoRESUMO
Diabetic nephropathy remains an area of high unmet medical need, with current therapies that slow down, but do not prevent, the progression of disease. A reduced phosphorylation state of adenosine monophosphate-activated protein kinase (AMPK) has been correlated with diminished kidney function in both humans and animal models of renal disease. Here, we describe the identification of novel, potent, small molecule activators of AMPK that selectively activate AMPK heterotrimers containing the ß1 subunit. After confirming that human and rodent kidney predominately express AMPK ß1, we explore the effects of pharmacological activation of AMPK in the ZSF1 rat model of diabetic nephropathy. Chronic administration of these direct activators elevates the phosphorylation of AMPK in the kidney, without impacting blood glucose levels, and reduces the progression of proteinuria to a greater degree than the current standard of care, angiotensin-converting enzyme inhibitor ramipril. Further analyses of urine biomarkers and kidney tissue gene expression reveal AMPK activation leads to the modulation of multiple pathways implicated in kidney injury, including cellular hypertrophy, fibrosis, and oxidative stress. These results support the need for further investigation into the potential beneficial effects of AMPK activation in kidney disease.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Aminopiridinas/farmacologia , Nefropatias Diabéticas/tratamento farmacológico , Ativadores de Enzimas/farmacologia , Indóis/farmacologia , Rim/efeitos dos fármacos , Aminopiridinas/uso terapêutico , Animais , Tamanho Celular , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Ativação Enzimática , Fibrose , Humanos , Indóis/uso terapêutico , Isoenzimas/metabolismo , Rim/metabolismo , Rim/patologia , Testes de Função Renal , Macaca fascicularis , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Fosforilação , Proteinúria/tratamento farmacológico , Proteinúria/metabolismo , Ratos , Especificidade da EspécieRESUMO
Targeting of the human ribosome is an unprecedented therapeutic modality with a genome-wide selectivity challenge. A liver-targeted drug candidate is described that inhibits ribosomal synthesis of PCSK9, a lipid regulator considered undruggable by small molecules. Key to the concept was the identification of pharmacologically active zwitterions designed to be retained in the liver. Oral delivery of the poorly permeable zwitterions was achieved by prodrugs susceptible to cleavage by carboxylesteraseâ 1. The synthesis of select tetrazole prodrugs was crucial. A cell-free inâ vitro translation assay containing human cell lysate and purified target mRNA fused to a reporter was used to identify active zwitterions. Inâ vivo PCSK9 lowering by oral dosing of the candidate prodrug and quantification of the drug fraction delivered to the liver utilizing an oral positron emission tomography 18 F-isotopologue validated our liver-targeting approach.
Assuntos
Fígado/efeitos dos fármacos , Inibidores de PCSK9 , Pró-Proteína Convertase 9/biossíntese , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Dose-Resposta a Droga , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Fígado/enzimologia , Fígado/metabolismo , Estrutura Molecular , Pró-Proteína Convertase 9/metabolismo , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-AtividadeAssuntos
Histona Desacetilases/farmacologia , Hipertensão Pulmonar/terapia , Fatores de Transcrição MEF2/farmacologia , Animais , Modelos Animais de Doenças , Imunofluorescência , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Hipertensão Pulmonar/genética , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/metabolismo , CamundongosRESUMO
The continued emergence of highly pathogenic viruses, which either thwart immune- and small molecule-based therapies or lack interventions entirely, mandates alternative approaches, particularly for prompt and facile pre- and post-exposure prophylaxis. Many highly pathogenic viruses, including coronaviruses, employ the six-helix bundle heptad repeat membrane fusion mechanism to achieve infection. Although heptad-repeat-2 decoys can inhibit viral entry by blocking six-helix bundle assembly, the biophysical and pharmacologic liabilities of peptides have hindered their clinical development. Here, we develop a chemically stapled lipopeptide inhibitor of SARS-CoV-2 as proof-of-concept for the platform. We show that our lead compound blocks infection by a spectrum of SARS-CoV-2 variants, exhibits mucosal persistence upon nasal administration, demonstrates enhanced stability compared to prior analogs, and mitigates infection in hamsters. We further demonstrate that our stapled lipopeptide platform yields nanomolar inhibitors of respiratory syncytial, Ebola, and Nipah viruses by targeting heptad-repeat-1 domains, which exhibit strikingly low mutation rates, enabling on-demand therapeutic intervention to combat viral outbreaks.
Assuntos
Infecções por Coronavirus , Lipopeptídeos , Humanos , Lipopeptídeos/farmacologia , Lipopeptídeos/uso terapêutico , Lipopeptídeos/química , Pandemias/prevenção & controleRESUMO
A new series of CB(1) receptor antagonists incorporating an imidazole-based isosteric replacement for the hydrazide moiety of rimonabant (SR141716) is disclosed. Members of this imidazole series possess potent/selective binding to the rCB(1) receptor and exhibit potent hCB(1) functional activity. Isopropyl analog 9a demonstrated activity in the tetrad assay and was orally-active in a food intake model.
Assuntos
Imidazóis/química , Imidazóis/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/metabolismo , Animais , Humanos , Imidazóis/farmacocinética , Modelos Moleculares , Conformação Molecular , Piperidinas/farmacocinética , Pirazóis/farmacocinética , Ratos , Rimonabanto , Relação Estrutura-AtividadeRESUMO
Recent large-scale genetic sequencing efforts have identified rare coding variants in genes in the triglyceride-rich lipoprotein (TRL) clearance pathway that are protective against coronary heart disease (CHD), independently of LDL cholesterol (LDL-C) levels. Insight into the mechanisms of protection of these variants may facilitate the development of new therapies for lowering TRL levels. The gene APOC3 encodes apoC-III, a critical inhibitor of triglyceride (TG) lipolysis and remnant TRL clearance. Here we report a detailed interrogation of the mechanism of TRL lowering by the APOC3 Ala43Thr (A43T) variant, the only missense (rather than protein-truncating) variant in APOC3 reported to be TG lowering and protective against CHD. We found that both human APOC3 A43T heterozygotes and mice expressing human APOC3 A43T display markedly reduced circulating apoC-III levels. In mice, this reduction is due to impaired binding of A43T apoC-III to lipoproteins and accelerated renal catabolism of free apoC-III. Moreover, the reduced content of apoC-III in TRLs resulted in accelerated clearance of circulating TRLs. On the basis of this protective mechanism, we developed a monoclonal antibody targeting lipoprotein-bound human apoC-III that promotes circulating apoC-III clearance in mice expressing human APOC3 and enhances TRL catabolism in vivo. These data reveal the molecular mechanism by which a missense variant in APOC3 causes reduced circulating TG levels and, hence, protects from CHD. This protective mechanism has the potential to be exploited as a new therapeutic approach to reduce apoC-III levels and circulating TRL burden.
Assuntos
Apolipoproteína C-III/genética , Lipoproteínas/metabolismo , Mutação de Sentido Incorreto , Triglicerídeos/metabolismo , Idoso , Animais , Anticorpos Monoclonais/farmacologia , Apolipoproteína C-III/efeitos dos fármacos , Apolipoproteínas B/metabolismo , HDL-Colesterol/metabolismo , Cromatografia Líquida , Simulação por Computador , Doença das Coronárias/genética , Estudos Transversais , Feminino , Humanos , Immunoblotting , Metabolismo dos Lipídeos/genética , Lipoproteínas/efeitos dos fármacos , Lipoproteínas VLDL/metabolismo , Masculino , Espectrometria de Massas , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Pessoa de Meia-Idade , Fatores de Proteção , Espectrometria de Massas em TandemRESUMO
UNLABELLED: CP432 is a newly discovered, nonprostanoid EP4 receptor selective prostaglandin E2 agonist. CP432 stimulates trabecular and cortical bone formation and restores bone mass and bone strength in aged ovariectomized rats with established osteopenia. INTRODUCTION: The purpose of this study was to determine whether a newly discovered, nonprostanoid EP4 receptor selective prostaglandin E2 (PGE2) agonist, CP432, could produce bone anabolic effects in aged, ovariectomized (OVX) rats with established osteopenia. MATERIALS AND METHODS: CP432 at 0.3, 1, or 3 mg/kg/day was given for 6 weeks by subcutaneous injection to 12-month-old rats that had been OVX for 8.5 months. The effects on bone mass, bone formation, bone resorption, and bone strength were determined. RESULTS: Total femoral BMD increased significantly in OVX rats treated with CP432 at all doses. CP432 completely restored trabecular bone volume of the third lumbar vertebral body accompanied with a dose-dependent decrease in osteoclast number and osteoclast surface and a dose-dependent increase in mineralizing surface, mineral apposition rate, and bone formation rate-tissue reference in OVX rats. CP432 at 1 and 3 mg/kg/day significantly increased total tissue area, cortical bone area, and periosteal and endocortical bone formation in the tibial shafts compared with both sham and OVX controls. CP432 at all doses significantly and dose-dependently increased ultimate strength in the fifth lumber vertebral body compared with both sham and OVX controls. At 1 and 3 mg/kg/day, CP432 significantly increased maximal load in a three-point bending test of femoral shaft compared with both sham and OVX controls. CONCLUSIONS: CP432 completely restored trabecular and cortical bone mass and strength in established osteopenic, aged OVX rats by stimulating bone formation and inhibiting bone resorption on trabecular and cortical surfaces.
Assuntos
Envelhecimento/fisiologia , Densidade Óssea/efeitos dos fármacos , Doenças Ósseas Metabólicas/tratamento farmacológico , Dinoprostona/agonistas , Osteogênese/efeitos dos fármacos , Receptores de Prostaglandina E/agonistas , Receptores de Prostaglandina E/metabolismo , Animais , Peso Corporal , Densidade Óssea/fisiologia , Modelos Animais de Doenças , Feminino , Fêmur/anatomia & histologia , Vértebras Lombares/anatomia & histologia , Estrutura Molecular , Tamanho do Órgão/efeitos dos fármacos , Ovariectomia , Ratos , Ratos Sprague-Dawley , Receptores de Prostaglandina E Subtipo EP4 , Especificidade por Substrato , Tíbia/anatomia & histologiaRESUMO
To investigate the anorectic potential of NPY5 receptor antagonists, we have profiled the in vitro and in vivo properties of 3-[2-[6-(2-tert-butoxyethoxy)pyridin-3-yl]-1H-imidazol-4-yl]benzonitrile hydrochloride salt (1). This compound was found to have excellent NPY5 receptor affinity and selectivity, potent functional antagonism, and good peripheral and central nervous system exposure in rats. This compound attenuated bovine pancreatic polypeptide induced food intake in rats but failed to demonstrate anorectic activity in rodent natural feeding models.
Assuntos
Imidazóis/síntese química , Nitrilas/síntese química , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Animais , Encéfalo/metabolismo , Cálcio/metabolismo , Bovinos , Líquido Cefalorraquidiano/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Imidazóis/farmacocinética , Imidazóis/farmacologia , Técnicas In Vitro , Masculino , Nitrilas/farmacocinética , Nitrilas/farmacologia , Polipeptídeo Pancreático/farmacologia , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Receptores de Neuropeptídeo Y/metabolismo , Distribuição Tecidual , Células Tumorais CultivadasRESUMO
Glucokinase is a key regulator of glucose homeostasis, and small molecule allosteric activators of this enzyme represent a promising opportunity for the treatment of type 2 diabetes. Systemically acting glucokinase activators (liver and pancreas) have been reported to be efficacious but in many cases present hypoglycaemia risk due to activation of the enzyme at low glucose levels in the pancreas, leading to inappropriately excessive insulin secretion. It was therefore postulated that a liver selective activator may offer effective glycemic control with reduced hypoglycemia risk. Herein, we report structure-activity studies on a carboxylic acid containing series of glucokinase activators with preferential activity in hepatocytes versus pancreatic ß-cells. These activators were designed to have low passive permeability thereby minimizing distribution into extrahepatic tissues; concurrently, they were also optimized as substrates for active liver uptake via members of the organic anion transporting polypeptide (OATP) family. These studies lead to the identification of 19 as a potent glucokinase activator with a greater than 50-fold liver-to-pancreas ratio of tissue distribution in rodent and non-rodent species. In preclinical diabetic animals, 19 was found to robustly lower fasting and postprandial glucose with no hypoglycemia, leading to its selection as a clinical development candidate for treating type 2 diabetes.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Ativadores de Enzimas/síntese química , Glucoquinase/metabolismo , Hepatócitos/metabolismo , Hipoglicemiantes/síntese química , Imidazóis/síntese química , Ácidos Nicotínicos/síntese química , Sítio Alostérico , Animais , Glicemia/metabolismo , Cães , Ativadores de Enzimas/farmacocinética , Ativadores de Enzimas/farmacologia , Haplorrinos , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Imidazóis/farmacocinética , Imidazóis/farmacologia , Técnicas In Vitro , Células Secretoras de Insulina/metabolismo , Masculino , Modelos Moleculares , Ácidos Nicotínicos/farmacocinética , Ácidos Nicotínicos/farmacologia , Transportadores de Ânions Orgânicos/metabolismo , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Estereoisomerismo , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
Acyl-CoA:diacylglycerol acyltransferase-1 (DGAT-1) catalyzes the final committed step in the biosynthesis of triglycerides. DGAT-1 knockout mice have been shown to be resistant to diet-induced obesity and have increased insulin sensitivity. Thus, inhibition of DGAT-1 may represent an attractive target for the treatment of obesity or type II diabetes. Herein, we report the discovery and characterization of a potent and selective DGAT-1 inhibitor PF-04620110 (3). Compound 3 inhibits DGAT-1 with an IC50 of 19 nM and shows high selectivity versus a broad panel of off-target pharmacologic end points. In vivo DGAT-1 inhibition has been demonstrated through reduction of plasma triglyceride levels in rodents at doses of ≥0.1 mg/kg following a lipid challenge. On the basis of this pharmacologic and pharmacokinetic profile, compound 3 has been advanced to human clinical studies.
RESUMO
We report the structure-activity relationships, design, and synthesis of the novel cannabinoid type 1 (CB1) receptor antagonist 3a (CP-945,598). Compound 3a showed subnanomolar potency at human CB1 receptors in binding (Ki = 0.7 nM) and functional assays (Ki = 0.12 nM). In vivo, compound 3a reversed cannabinoid agonist-mediated responses, reduced food intake, and increased energy expenditure and fat oxidation in rodents.
Assuntos
Piperidinas/farmacologia , Purinas/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Animais , Cães , Descoberta de Drogas , Metabolismo Energético , Gorduras/metabolismo , Oxirredução , Piperidinas/química , Purinas/química , Relação Estrutura-AtividadeRESUMO
We report the design, synthesis, and structure-activity relationships of novel bicyclic lactam-based cannabinoid type 1 (CB(1)) receptor antagonists. Members of these series are potent, selective antagonists in in vitro/in vivo efficacy models of CB(1) antagonism and exhibit robust oral activity in rodent models of food intake. These efforts led to the identification of 19d, which has been advanced to human clinical trials for weight management.
Assuntos
Descoberta de Drogas , Lactamas/síntese química , Lactamas/farmacologia , Obesidade/tratamento farmacológico , Oxazepinas/síntese química , Oxazepinas/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Animais , Ensaios Clínicos como Assunto , Cristalografia por Raios X , Humanos , Lactamas/química , Lactamas/uso terapêutico , Oxazepinas/química , Oxazepinas/uso terapêutico , Pirazóis/síntese química , Pirazóis/química , Pirazóis/farmacologia , Pirazóis/uso terapêutico , RatosRESUMO
A novel series of heterocycle-based analogs were prepared and evaluated for their in vitro and in vivo biological activity as human beta(3)-adrenergic receptor (AR) agonists. Several analogs demonstrated potent agonist activity at the beta(3)-AR, functional selectivity against beta(1)- and beta(2)-ARs, and favorable pharmacokinetic profiles in vivo. Compound 17 increased oxygen consumption in rats, a measure of energy expenditure, with an ED(20%) of 2mg/kg.
Assuntos
Agonistas de Receptores Adrenérgicos beta 3 , Agonistas Adrenérgicos beta/uso terapêutico , Obesidade/tratamento farmacológico , Administração Oral , Agonistas Adrenérgicos beta/administração & dosagem , Agonistas Adrenérgicos beta/farmacocinética , Agonistas Adrenérgicos beta/farmacologia , Animais , Disponibilidade Biológica , RatosRESUMO
A series of ligands with varying heterocyclic cores and substituents that display a range of selectivity's (up to >100x) for ER-beta over ER-alpha are reported.
Assuntos
Receptor beta de Estrogênio/metabolismo , Compostos Heterocíclicos/farmacocinética , Linhagem Celular Tumoral , Cristalografia por Raios X , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/química , Compostos Heterocíclicos/síntese química , Humanos , Indicadores e Reagentes , Cinética , Ligantes , Moduladores Seletivos de Receptor Estrogênico/química , Relação Estrutura-AtividadeRESUMO
A series of 2-heteroaryl-4-arylimidazoles with potent in vitro activity at the NPY5 receptor was developed. Introduction of electron-withdrawing groups on the 4-aryl ring led to a significant improvement of in vitro potency. Several analogues from this series had anorectic activity in rodent feeding models, but were also found to have undesired behavioral effects in spontaneous locomotor activity.
Assuntos
Imidazóis/química , Imidazóis/farmacologia , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Ratos , Relação Estrutura-AtividadeRESUMO
A series of sulfamide-based analogs related to L-796568 were prepared and evaluated for their biological activity at the human beta(3)-adrenergic receptor (AR). This modification allows for a significant reduction in molecular weight, while maintaining single-digit nanomolar potencies at the beta(3)-AR and high selectivities versus the beta(2)- or beta(3)-AR.
Assuntos
Agonistas de Receptores Adrenérgicos beta 3 , Agonistas Adrenérgicos beta/química , Sulfonamidas/química , Agonistas Adrenérgicos beta/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Animais , Humanos , Consumo de Oxigênio/efeitos dos fármacos , Consumo de Oxigênio/fisiologia , Ratos , Receptores Adrenérgicos beta 3/metabolismo , Sulfonamidas/metabolismo , Sulfonamidas/farmacologiaRESUMO
Beginning with carbazole 1a, the amide and alkyl substituents were optimized to maintain potency while adding solubilizing groups. Efforts to replace the 3-amino-9-ethylcarbazole core, a known carcinogen, used the SAR generated in the carbazole series for guidance and led to the synthesis of a number of core-modified analogues. In addition, an isosteric series, in which the amide was replaced with an imidazole, was prepared. Two potent new series lacking the putative toxicophore were identified from these endeavors.
Assuntos
Amidas/química , Amidas/farmacologia , Carbazóis/química , Carbazóis/farmacologia , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Animais , Cálcio/química , Cálcio/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Imidazóis/química , Imidazóis/farmacologia , Concentração Inibidora 50 , Masculino , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Solubilidade , Relação Estrutura-AtividadeRESUMO
Two series of 6-hydroxy and 7-hydroxy tetrahydroisoquinolines were prepared. Evaluating a range of C-1, C-4, and N-substituents led to the discovery of ER alpha and ER beta selective analogs.