RESUMO
Previous investigations in our laboratories resulted in the discovery of a novel series of potent nucleoside inhibitors of Hepatitis C virus (HCV) NS5B polymerase bearing tetracyclic 7-substituted 7-deaza-adenine nucleobases. The planarity of such modified systems was suggested to play a role in the high inhibitory potency observed. This paper describes how we envisaged to maintain the desired planarity of the modified nucleobase by means of an intra-molecular H-bond, engaging a H-bond donor atom on an appropriately substituted 7-heterocyclic residue with the adjacent amino group of the nucleobase. The success of this strategy is reflected by the identification of several novel potent nucleoside inhibitors of HCV NS5B bearing a 7-heterocyclic substituted 7-deaza-adenine nucleobase. Amongst these, the 1,2,4-oxadiazole analog 11 showed high antiviral potency against HCV replication in replicon cells and efficient conversion to the corresponding NTP in vivo, with high and sustained levels of NTP measured in rat liver following intravenous and oral administration.
Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Hepacivirus/efeitos dos fármacos , Nucleosídeos/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/síntese química , Antivirais/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Nucleosídeos/síntese química , Nucleosídeos/química , Replicon/efeitos dos fármacos , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacosRESUMO
A series of 2-pyrrolidinyl-N-methyl pyrimidones HIV integrase inhibitors has been explored leading to the identification of derivative 13, which showed high activity at inhibiting viral replication in cell culture, favorable pharmacokinetic profile in two preclinical species, and an attractive profile against a panel of HIV-integrase mutants.
Assuntos
Inibidores de Integrase de HIV/farmacologia , Pirimidinonas/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Inibidores de Integrase de HIV/administração & dosagem , Inibidores de Integrase de HIV/farmacocinética , Pirimidinonas/administração & dosagem , Pirimidinonas/farmacocinética , RatosRESUMO
Herein we describe the discovery of a novel series of pyrrolo[1,2-a]pyrazin-1(2H)-one PARP inhibitors. Optimization led to compounds that display excellent PARP-1 enzyme potency and inhibit the proliferation of BRCA deficient cells in the low double-digit nanomolar range showing excellent selectivity over BRCA proficient cancer cells.
Assuntos
Inibidores de Poli(ADP-Ribose) Polimerases , Pirazinas/química , Pirazinas/metabolismo , Animais , Proteína BRCA1/deficiência , Proteína BRCA1/metabolismo , Linhagem Celular Tumoral , Cristalografia por Raios X , Células HeLa , Humanos , Indolizinas/química , Indolizinas/metabolismo , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Poli(ADP-Ribose) Polimerase-1 , Poli(ADP-Ribose) Polimerases/metabolismo , Ligação Proteica/fisiologia , Ratos , Relação Estrutura-AtividadeRESUMO
A novel class of tetrahydro-pyrazinopyrimidine-2-carboxamides have been identified as HIV-1 integrase inhibitors. Optimization of the initial lead culminated in the discovery of a series of compounds with high potency on the enzyme and an antiviral cell-based activity equivalent to that showed by Raltegravir, the first in class HIV-1 integrase inhibitor.
Assuntos
Inibidores de Integrase de HIV/síntese química , Pirazinas/síntese química , Pirimidinas/síntese química , Animais , Linhagem Celular , Química Farmacêutica/métodos , Desenho de Fármacos , Inibidores de Integrase de HIV/farmacologia , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética/métodos , Modelos Químicos , Nitrogênio/química , Pirazinas/farmacologia , Pirimidinas/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A variety of new prodrugs of 2'-methyl cytidine based on acyloxy ethylamino phosphoramidates have been synthesized and tested in vitro and in vivo for their biological activity. Compared with the parent drug a 10- to 20-fold increase in formation of nucleotide triphosphate in rat and human hepatocytes could be achieved.
Assuntos
Amidas/síntese química , Citidina/análogos & derivados , Citidina/síntese química , Ácidos Fosfóricos/síntese química , Pró-Fármacos/síntese química , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Proteínas não Estruturais Virais/antagonistas & inibidores , Amidas/farmacologia , Animais , Células Cultivadas , Citidina/farmacologia , Cães , Avaliação Pré-Clínica de Medicamentos/métodos , Hepacivirus/efeitos dos fármacos , Hepacivirus/enzimologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/enzimologia , Hepatócitos/virologia , Humanos , Ácidos Fosfóricos/farmacologia , Pró-Fármacos/farmacologia , RNA Polimerase Dependente de RNA/metabolismo , Coelhos , Ratos , Proteínas não Estruturais Virais/metabolismoRESUMO
HIV integrase is one of the three enzymes encoded by HIV genome and is essential for viral replication, but integrase inhibitors as marketed drugs have just very recently started to emerge. In this study, we show the evolution from the N-methylpyrimidinone structure to bicyclic pyrimidinones. Introduction of a suitably substituted amino moiety modulated the physical-chemical properties of the molecules and conferred nanomolar activity in the inhibition of spread of HIV-1 infection in cell culture. An extensive SAR study led to sulfamide (R)- 22b, which inhibited the strand transfer with an IC50 of 7 nM and HIV infection in MT4 cells with a CIC95 of 44 nM, and ketoamide (S)- 28c that inhibited strand transfer with an IC50 of 12 nM and the HIV infection in MT4 cells with a CIC95 of 13 nM and exhibited a good pharmacokinetic profile when dosed orally to preclinical species.
Assuntos
Aminopiridinas/síntese química , Azepinas/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Inibidores de Integrase de HIV/síntese química , Integrase de HIV/metabolismo , Pirimidinonas/síntese química , Administração Oral , Aminopiridinas/farmacocinética , Aminopiridinas/farmacologia , Animais , Azepinas/farmacocinética , Azepinas/farmacologia , Disponibilidade Biológica , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linhagem Celular , Cães , Integrase de HIV/genética , Inibidores de Integrase de HIV/farmacocinética , Inibidores de Integrase de HIV/farmacologia , HIV-1/efeitos dos fármacos , Humanos , Macaca mulatta , Microssomos Hepáticos/metabolismo , Pirimidinonas/farmacocinética , Pirimidinonas/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of novel 2-(t)butyl-N-methyl pyrimidone HIV-1 integrase inhibitors have been identified. Optimization of the initial lead resulted in compounds such as 9d and 14a, which showed high levels of activity in cell culture inhibiting viral replication with CIC(95) of 10nM in the presence of 50% normal human serum.
Assuntos
Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/farmacologia , Pirimidinonas/síntese química , Pirimidinonas/farmacologia , Amidas/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Inibidores de Integrase de HIV/química , Humanos , Metilação , Estrutura Molecular , Pirimidinonas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Histone deacetylase (HDAC) inhibitors offer a promising strategy for cancer therapy and the first generation HDAC inhibitors are currently in the clinic. Herein we describe the optimization of a series of ketone small molecule HDAC inhibitors leading to potent and selective class I HDAC inhibitors with good dog PK.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores de Histona Desacetilases , Histona Desacetilases/metabolismo , Cetonas/química , Administração Oral , Animais , Proliferação de Células , Cães , Inibidores Enzimáticos/farmacologia , Células HeLa , Histona Desacetilase 1 , Humanos , Concentração Inibidora 50 , Modelos Químicos , Ratos , Proteínas Recombinantes/química , Zinco/químicaRESUMO
AIM: To evaluate accuracy of endorectal ultrasonography (ERUS) both in staging and restaging rectal cancer after neoadjuvant chemoradiotherapy treatment. METHODS: In a group of 80 patients with rectal cancer, we retrospectively selected 67 patients and divided in two groups: 41 patients affected by a stage I were investigated with a single preoperative endorectal sonography; 26 patients with locally advanced rectal cancer (stage II or more) were restaged after neoadjuvant treatment, which consisted of 5,040 cGy in 28 daily fractions associated with continuous infusion of 5-Fluorouracil. All patients underwent surgery and ERUS findings were subsequently compared with histological findings. RESULTS: Diagnostic accuracy of ERUS in the first group of patients was high: in fact T-staging was accurate in 85% of cases. Results in the second group were significantly less accurate, with a correct T-staging just for 47% of cases. Nodes involvement was correctly evaluated in 86% of cases for the first group and in 63% of cases for the second one. CONCLUSIONS: Endorectal sonography is a valid staging modality for early rectal malignancy. Advanced cancer is treated with neoadjuvant preoperative chemoradiotherapy which is associated with better outcome than postoperative treatment. We found endorectal sonography, based on the layer model of rectal wall, often fails restaging and we think we have to develop new criteria for a correct preoperative assessment after neoadjuvant chemoradiation. KEY WORDS: Endorectal ultrasonography, Neoadjuvant chemoradiotherapy, Rectal cancer, Staging.
Assuntos
Quimiorradioterapia , Endossonografia , Terapia Neoadjuvante , Cuidados Pós-Operatórios , Cuidados Pré-Operatórios , Neoplasias Retais/diagnóstico por imagem , Neoplasias Retais/terapia , Quimiorradioterapia/métodos , Endossonografia/métodos , Feminino , Humanos , Masculino , Terapia Neoadjuvante/métodos , Estadiamento de Neoplasias , Cuidados Pós-Operatórios/métodos , Cuidados Pré-Operatórios/métodos , Neoplasias Retais/patologia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral genome and has been a prime target for drug discovery efforts. Here, we report on the further development of tetracyclic indole inhibitors, binding to an allosteric site on the thumb domain. Structure-activity relationship (SAR) studies around an indolo-benzoxazocine scaffold led to the identification of compound 33 (MK-3281), an inhibitor with good potency in the HCV subgenomic replication assay and attractive molecular properties suitable for a clinical candidate. The compound caused a consistent decrease in viremia in vivo using the chimeric mouse model of HCV infection.
Assuntos
Antivirais/síntese química , Hepacivirus/efeitos dos fármacos , Indóis/síntese química , Oxazocinas/síntese química , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Proteínas não Estruturais Virais/antagonistas & inibidores , Administração Oral , Animais , Antivirais/farmacocinética , Antivirais/farmacologia , Disponibilidade Biológica , Linhagem Celular Tumoral , Cristalografia por Raios X , Cães , Hepacivirus/enzimologia , Hepacivirus/fisiologia , Humanos , Indóis/farmacocinética , Indóis/farmacologia , Macaca mulatta , Camundongos , Camundongos SCID , Camundongos Transgênicos , Modelos Moleculares , Estrutura Molecular , Oxazocinas/farmacocinética , Oxazocinas/farmacologia , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Viremia/tratamento farmacológico , Viremia/virologia , Replicação Viral/efeitos dos fármacosRESUMO
AIM: The aim of this study was to assess the clinical relevance of MR and transrectal ultrasonography (TRUS) imaging of rectal villous tumours to elucidate the correlation between imaging results and specific histopathological tumour features, such as tumour size (T) and lymph node involvement (N), in order to establish the better technique for the pre-surgical patient evaluation. PATIENTS AND METHODS: 23 cases of villous tumours of the rectum were studied with phased-array MR and TRUS. All patients underwent either surgical or endoscopic treatment. Final diagnosis was based on histopathological results. In particular, the following features were characterized by the imaging techniques mentioned above: lesion site, distance between lesion and ano-rectal junction, size, morphology and contrast enhancement of lesions, fluid layer around the lesion, alterations of the deep layers of the rectal wall, sphincter infiltration, presence or absence of mesorectal, iliac and obturatory lymphnode involvement. RESULTS: Histology established muscular involvement in 7 cases (T2), perirectal fat infiltration in 1 case (T3); in the remaining 15 cases, staging was Tis-T1. In 17/23 cases (73.9%) the lesions were correctly staged with both imaging techniques, whereas in 5/23 cases (21.7%) the lesions were overstaged. No cases were understaged. TRUS concorded with histological exams in 17/23 cases (73.9%). 5/23 cases (21.7%) were overstaged and 1/23 (4%) was understaged. MR and TRUS were in accordance in 20/23 cases (86.9%). DISCUSSION: Considering the frequent degeneration of villous tumours, correct preoperative identification and precise evaluation of these lesions, such as the detection of rectal wall invasion, is essential in deciding optimal treatment strategy. MRI and TRUS allow the identification of specific features of villous tumours and of malignant degeneration, allowing for a correct local disease staging.
Assuntos
Adenoma Viloso/diagnóstico , Neoplasias Retais/diagnóstico , Reto/diagnóstico por imagem , Reto/patologia , Ultrassonografia/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Estatística como AssuntoRESUMO
The purpose of this study was to investigate the in vivo absorption enhancement of a nucleoside (phosphoramidate prodrug of 2'-methyl-cytidine) anti-viral agent of proven efficacy by means of intestinal permeation enhancers. Natural nucleosides are hydrophilic molecules that do not rapidly penetrate cell membranes by diffusion and their absorption relies on specialized transporters. Therefore, the oral absorption of nucleoside prodrugs and the target organ concentration of the biologically active nucleotide can be limited due to poor permeation across the intestinal epithelium. In the present study, the specificity, concentration dependence, and effect of four classes of absorption promoters, i.e. fatty acids, steroidal detergents, mucoadhesive polymers, and secretory transport inhibitors, were evaluated in a rat in vivo model. Sodium caprate and alpha-tocopheryl-polyethyleneglycol-1000-succinate (TPGS) showed a significant effect in increasing liver concentration of nucleotide (5-fold). These results suggested that both excipients might be suited in a controlled release matrix for the synchronous release of the drug and absorption promoter directly to the site of absorption and highlights that the effect is strictly dependent on the absorption promoter dose. The feasibility of such a formulation approach in humans was evaluated with the aim of developing a solid dosage form for the peroral delivery of nucleosides and showed that these excipients do provide a potential valuable tool in pre-clinical efficacy studies to drive discovery programs forward.
Assuntos
Citidina/análogos & derivados , Absorção Intestinal/efeitos dos fármacos , Absorção Intestinal/fisiologia , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Animais , Células CACO-2 , Citidina/química , Citidina/farmacocinética , Sinergismo Farmacológico , Humanos , Masculino , Camundongos , Camundongos Knockout , Ratos , Ratos Sprague-DawleyRESUMO
Our laboratories recently reported the discovery of P2-P4 macrocyclic inhibitors of HCV NS3/4A protease, characterized by high levels of potency and liver exposure. Within this novel class of inhibitors, we here describe the identification of a structurally diverse series of compounds featuring a 2-amino-1,3-thiazole as replacement of the carbamate in P4. Optimization studies focused on structural modifications in the P3, P2, and P1 regions of the macrocycle as well as on the linker chain and resulted in the discovery of several analogues characterized by excellent levels of enzyme and cellular activity. Among these, compound 59 displayed an attractive pharmacokinetic profile in preclinical species and showed sustained liver levels following oral administration in rats.
Assuntos
Carbamatos/química , Proteínas de Transporte/antagonistas & inibidores , Hepacivirus/enzimologia , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Tiazóis/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas Virais/antagonistas & inibidores , Animais , Proteínas de Transporte/química , Domínio Catalítico , Cães , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Compostos Macrocíclicos/farmacocinética , Modelos Moleculares , Inibidores de Proteases/química , Inibidores de Proteases/farmacocinética , Inibidores de Proteases/farmacologia , Ratos , Proteínas não Estruturais Virais/química , Proteínas Virais/químicaRESUMO
The optimization of a potent, class I selective ketone HDAC inhibitor is shown. It possesses optimized pharmacokinetic properties in preclinical species, has a clean off-target profile, and is negative in a microbial mutagenicity (Ames) test. In a mouse xenograft model it shows efficacy comparable to that of vorinostat at a 10-fold reduced dose.
Assuntos
Antineoplásicos/farmacocinética , Inibidores Enzimáticos/farmacocinética , Inibidores de Histona Desacetilases , Quinolinas/farmacocinética , Animais , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Cães , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Células HeLa , Humanos , Camundongos , Quinolinas/síntese química , RatosRESUMO
In a follow-up to our recent disclosure of P2-P4 macrocyclic inhibitors of the hepatitis C virus (HCV) NS3 protease (e.g., 1, Chart 1), we report a new but related compound series featuring a basic amine at the N-terminus of the P3-amino acid residue. Replacement of the electroneutral P3-amino acid capping group (which is a feature of almost all tripeptide-like inhibitors of NS3 reported to date) with a basic group is not only tolerated but can result in advantageous cell based potency. Optimization of this new class of P3-amine based inhibitors gave compounds such as 25 and 26 that combine excellent cell based activity with pharmacokinetic properties that are attractive for an antiviral targeting HCV.
Assuntos
Aminas/síntese química , Antivirais/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Aminas/farmacocinética , Aminas/farmacologia , Animais , Antivirais/farmacocinética , Antivirais/farmacologia , Cães , Descoberta de Drogas , Masculino , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
The application of a phosphoramidate prodrug approach to 2'-C-methylcytidine (NM107), the first nucleoside inhibitor of the hepatitis C virus (HCV) NS5B polymerase, is reported. 2'-C-Methylcytidine, as its valyl ester prodrug (NM283), was efficacious in reducing the viral load in patients infected with HCV. Several of the phosphoramidates prepared demonstrated a 10- to 200-fold superior potency with respect to the parent nucleoside in the cell-based replicon assay. This is due to higher levels of 2'-C-methylcytidine triphosphate in the cells. These prodrugs are efficiently activated and converted to the triphosphate in hepatocytes of several species. Our SAR studies ultimately led to compounds that gave high levels of NTP in hamster and rat liver after subcutaneous dosing and that were devoid of the toxic phenol moiety usually found in ProTides.
Assuntos
Amidas/metabolismo , Amidas/uso terapêutico , Antivirais/metabolismo , Citidina/análogos & derivados , Hepatite C/tratamento farmacológico , Ácidos Fosfóricos/metabolismo , Ácidos Fosfóricos/uso terapêutico , Pró-Fármacos/metabolismo , Pró-Fármacos/uso terapêutico , Amidas/farmacologia , Amidas/toxicidade , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Antivirais/toxicidade , Linhagem Celular , Citidina/metabolismo , Citidina/farmacologia , Citidina/uso terapêutico , Citidina/toxicidade , Hepacivirus/efeitos dos fármacos , Hepacivirus/fisiologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/virologia , Humanos , Ácidos Fosfóricos/farmacologia , Ácidos Fosfóricos/toxicidade , Polifosfatos/metabolismo , Pró-Fármacos/farmacologia , Pró-Fármacos/toxicidade , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
Infections caused by the hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The NS5B polymerase of HCV is responsible for the replication of viral RNA and has been a prime target in the search for novel treatment options. We had discovered allosteric finger-loop inhibitors based on a thieno[3,2-b]pyrrole scaffold as an alternative to the related indole inhibitors. Optimization of the thienopyrrole series led to several N-acetamides with submicromolar potency in the cell-based replicon assay, but they lacked oral bioavailability in rats. By linking the N4-position to the ortho-position of the C5-aryl group, we were able to identify the tetracyclic thienopyrrole 40, which displayed a favorable pharmacokinetic profile in rats and dogs and is equipotent with recently disclosed finger-loop inhibitors based on an indole scaffold.
Assuntos
Antivirais/farmacologia , Azocinas/farmacologia , Inibidores Enzimáticos/farmacologia , Hepacivirus/efeitos dos fármacos , Pirróis/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Regulação Alostérica/efeitos dos fármacos , Animais , Antivirais/química , Antivirais/farmacocinética , Azocinas/química , Cães , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Hepacivirus/enzimologia , Humanos , Conformação Proteica , Pirróis/química , Pirróis/farmacocinética , Ratos , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/genéticaRESUMO
The currently approved treatment for hepatitis C virus infections is a combination of Ribavirin and pegylated Interferon. It leads to a sustained virologic response in approximately only half of the patients treated. For this reason there is an urgent need of new therapeutic agents. 2'-C-Methylcytidine is the first nucleoside inhibitor of the HCV NS5B polymerase that was efficacious in reducing the viral load in patients infected with HCV. The application of a monophosphate prodrug approach based on unprecedented cyclic phosphoramidates is reported. Our SAR studies led to compounds that are efficiently converted to the active triphosphate in human hepatocytes.
Assuntos
Antivirais/metabolismo , Antivirais/farmacologia , Citidina/análogos & derivados , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Pró-Fármacos/farmacologia , Animais , Antivirais/administração & dosagem , Antivirais/química , Cricetinae , Citidina/administração & dosagem , Citidina/química , Citidina/metabolismo , Citidina/farmacologia , Estabilidade de Medicamentos , Hepatócitos/virologia , Humanos , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Relação Estrutura-AtividadeRESUMO
Human immunodeficiency virus type-1 (HIV-1) integrase is one of the three virally encoded enzymes required for replication and therefore a rational target for chemotherapeutic intervention in the treatment of HIV-1 infection. We report here the discovery of Raltegravir, the first HIV-integrase inhibitor approved by FDA for the treatment of HIV infection. It derives from the evolution of 5,6-dihydroxypyrimidine-4-carboxamides and N-methyl-4-hydroxypyrimidinone-carboxamides, which exhibited potent inhibition of the HIV-integrase catalyzed strand transfer process. Structural modifications on these molecules were made in order to maximize potency as HIV-integrase inhibitors against the wild type virus, a selection of mutants, and optimize the selectivity, pharmacokinetic, and metabolic profiles in preclinical species. The good profile of Raltegravir has enabled its progression toward the end of phase III clinical trials for the treatment of HIV-1 infection and culminated with the FDA approval as the first HIV-integrase inhibitor for the treatment of HIV-1 infection.
Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/farmacologia , Pirrolidinonas/farmacologia , Administração Oral , Área Sob a Curva , Disponibilidade Biológica , Inibidores de Integrase de HIV/administração & dosagem , Inibidores de Integrase de HIV/farmacocinética , Inibidores de Integrase de HIV/uso terapêutico , Meia-Vida , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Pirrolidinonas/administração & dosagem , Pirrolidinonas/farmacocinética , Pirrolidinonas/uso terapêutico , Raltegravir PotássicoRESUMO
The only supernovae (SNe) to show gamma-ray bursts (GRBs) or early x-ray emission thus far are overenergetic, broad-lined type Ic SNe (hypernovae, HNe). Recently, SN 2008D has shown several unusual features: (i) weak x-ray flash (XRF), (ii) an early, narrow optical peak, (iii) disappearance of the broad lines typical of SN Ic HNe, and (iv) development of helium lines as in SNe Ib. Detailed analysis shows that SN 2008D was not a normal supernova: Its explosion energy (E approximately 6x10(51) erg) and ejected mass [ approximately 7 times the mass of the Sun (M(middle dot in circle))] are intermediate between normal SNe Ibc and HNe. We conclude that SN 2008D was originally a approximately 30 M(middle dot in circle) star. When it collapsed, a black hole formed and a weak, mildly relativistic jet was produced, which caused the XRF. SN 2008D is probably among the weakest explosions that produce relativistic jets. Inner engine activity appears to be present whenever massive stars collapse to black holes.