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1.
Clin Pharmacokinet ; 62(11): 1533-1550, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37776485

RESUMO

Ponesimod, a selective, rapidly reversible, and orally active, sphingosine-1 phosphate receptor (S1P) modulator, is indicated for the treatment of relapsing-remitting multiple sclerosis (RRMS). The clinical pharmacokinetics (PK) and pharmacodynamics (PD) of ponesimod was studied in 16 phase I, one phase II, and one phase III clinical studies. Ponesimod population PK was characterized by an open two-compartment disposition model with a terminal half-life of 33 h (accumulation factor of 2- to 2.6-fold), and fast and almost complete oral absorption (absolute oral bioavailability: 84%), reaching peak plasma and blood concentrations within 2-4 h. Ponesimod is highly metabolized, and the parent compound along with its two major (non-clinically active) metabolites are mainly excreted in the feces (recovery: 57.3-79.6%) and to a lesser extent in the urine (recovery: 10.3-18.4%). Additionally, the population PKPD model characterized the ponesimod effects on heart rate: a transient, dose-dependent decrease in heart rate in the first days of dosing, that is mitigated by administering the first doses of ponesimod treatment using a gradual up-titration schedule, before reaching the daily maintenance dose of 20 mg. This selected maintenance dose has been shown to be superior in reducing annualized relapse rate (ARR) when compared with teriflunomide in a pivotal phase III study. Furthermore, a dose-dependent reduction of peripheral lymphocyte counts that is sustained with continued daily oral dosing of ponesimod and is rapidly (4-7 days) reversible upon drug discontinuation has been characterized with an indirect response model.


Assuntos
Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Receptores de Esfingosina-1-Fosfato , Esclerose Múltipla/tratamento farmacológico , Receptores de Lisoesfingolipídeo/metabolismo , Tiazóis , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Fatores Imunológicos
2.
BMJ Case Rep ; 20182018 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-30209144

RESUMO

Over 200 000 surgeries for vaginal prolapse are done annually, and these are rarely urgent. However, when the rare event of bladder stones causes incarcerated procidentia, surgical intervention should not be delayed, due to unrelenting pain and end-organs effects. We present such a case below. A 71-year-old woman presents to our department with massive uterovaginal and rectal procidentia. This massive prolapse was found to be irreducible due to numerous dahllite stones in the bladder, and was causing obstructive uropathy with left-sided hydronephrosis. A multidisciplinary approach was necessary to surgically correct the prolapse and implement complete removal of all the stones. The simultaneous occurrence of uterovaginal prolapse, rectal prolapse and urolithiasis is uncommon. Stone formation is a result of chronically infected urine presenting a nidus for stone formation. This presentation has occurred very rarely over the last 70 years of the world's literature. Surgical cures can be achieved by either the vaginal or abdominal routes but should be treated emergently to alleviate pain, prevent renal impairment from obstructive uropathy and decrease infectious morbidity.


Assuntos
Prolapso de Órgão Pélvico/etiologia , Cálculos da Bexiga Urinária/complicações , Idoso , Diagnóstico Diferencial , Feminino , Procedimentos Cirúrgicos em Ginecologia/métodos , Humanos , Prolapso de Órgão Pélvico/cirurgia , Reto/cirurgia , Bexiga Urinária/cirurgia , Cálculos da Bexiga Urinária/cirurgia , Procedimentos Cirúrgicos Urológicos/métodos , Vagina/cirurgia
3.
ACS Med Chem Lett ; 9(7): 652-656, 2018 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-30034595

RESUMO

Identification of ligands that selectively activate the M1 muscarinic signaling pathway has been sought for decades to treat a range of neurological and cognitive disorders. Herein, we describe the optimization efforts focused on addressing key physicochemical and safety properties, ultimately leading to the clinical candidate MK-7622, a highly selective positive allosteric modulator of the M1 muscarinic receptor that has entered Phase II studies in patients with Alzheimer's disease.

4.
Pharm Res ; 31(12): 3445-60, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24980206

RESUMO

PURPOSE: To develop a tool based on siRNA-mediated knockdown of hepatic P450 oxidoreductase (POR) to decrease the CYP-mediated metabolism of small molecule drugs that suffer from rapid metabolism in vivo, with the aim of improving plasma exposure of these drugs. METHODS: siRNA against the POR gene was delivered using lipid nanoparticles (LNPs) into rats. The time course of POR mRNA knockdown, POR protein knockdown, and loss of POR enzyme activity was monitored. The rat livers were harvested to produce microsomes to determine the impact of POR knockdown on the metabolism of several probe substrates. Midazolam (a CYP3A substrate with high intrinsic clearance) was administered into LNP-treated rats to determine the impact of POR knockdown on midazolam pharmacokinetics. RESULTS: Hepatic POR mRNA and protein levels were significantly reduced by administering siRNA and the maximum POR enzyme activity reduction (~85%) occurred 2 weeks post-dose. In vitro analysis showed significant reductions in metabolism of probe substrates due to POR knockdown in liver, and in vivo POR knockdown resulted in greater than 10-fold increases in midazolam plasma concentrations following oral dosing. CONCLUSIONS: Anti-POR siRNA can be used to significantly reduce hepatic metabolism by various CYPs as well as greatly increase the bioavailability of high clearance compounds following an oral dose, thus enabling it to be used as a tool to increase drug exposure in vivo.


Assuntos
Sistema Enzimático do Citocromo P-450/genética , Técnicas de Silenciamento de Genes/métodos , RNA Interferente Pequeno/farmacologia , Animais , Química Farmacêutica , Diclofenaco/metabolismo , Técnicas In Vitro , Masculino , Microssomos/efeitos dos fármacos , Microssomos/enzimologia , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Midazolam/metabolismo , Nanopartículas , Ligação Proteica , Ratos
5.
ACS Med Chem Lett ; 5(5): 604-8, 2014 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-24900888

RESUMO

Selective activation of the M1 muscarinic receptor via positive allosteric modulation represents an original approach to treat the cognitive decline in patients with Alzheimer's disease. A series of naphthyl-fused 5-membered lactams were identified as a new class of M1 positive allosteric modulators and were found to possess good potency and in vivo efficacy.

6.
Bioorg Med Chem Lett ; 24(5): 1417-20, 2014 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-24485781

RESUMO

A series of methoxynaphthalene amides were prepared and evaluated as alternatives to quinolizidinone amide M1 positive allosteric modulators. A methoxy group was optimal for M1 activity and addressed key P-gp issues present in the aforementioned quinolizidinone amide series.


Assuntos
Amidas/química , Naftalenos/química , Quinolizidinas/química , Receptor Muscarínico M1/metabolismo , Regulação Alostérica , Amidas/síntese química , Amidas/metabolismo , Animais , Células CHO , Cricetinae , Cricetulus , Camundongos , Ligação Proteica , Receptor Muscarínico M1/química , Relação Estrutura-Atividade
7.
Eur J Pharmacol ; 724: 102-11, 2014 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-24374007

RESUMO

Glucocorticoids are used widely in the treatment of inflammatory diseases, but use is accompanied by a significant burden of adverse effects. It has been hypothesized that gene- and cell-specific regulation of the glucocorticoid receptor by small molecule ligands could be translated into a therapeutic with an improved risk-benefit profile. MK-5932 is a highly selective glucocorticoid receptor modulator that is anti-inflammatory in vivo with an improved profile on glucose metabolism: Bungard et al. (2011). Bioorg. Med. Chem. 19, 7374-7386. Here we describe the full biological profile of MK-5932. Cytokine production following lipopolysaccharide (LPS) challenge was blocked by MK-5932 in both rat and human whole blood. Oral administration reduced inflammatory cytokine levels in the serum of rats challenged with LPS. MK-5932 was anti-inflammatory in a rat contact dermatitis model, but was differentiated from 6-methylprednisolone by a lack of elevation of fasting insulin or glucose levels after 7 days of dosing, even at high exposure levels. In fact, animals in the vehicle group were consistently hyperglycemic at the end of the study, and MK-5932 normalized glucose levels in a dose-dependent manner. MK-5932 was also anti-inflammatory in the rat collagen-induced arthritis and adjuvant-induced arthritis models. In healthy dogs, oral administration of MK-5932 exerted acute pharmacodynamic effects with potency comparable to prednisone, but with important differences on neutrophil counts, again suggestive of a dissociated profile. Important gaps in our understanding of mechanism of action remain, but MK-5932 will be a useful tool in dissecting the mechanisms of glucose dysregulation by therapeutic glucocortiocids.


Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Benzamidas/uso terapêutico , Dermatite de Contato/tratamento farmacológico , Edema/tratamento farmacológico , Indazóis/uso terapêutico , Receptores de Glucocorticoides/metabolismo , Animais , Anti-Inflamatórios/sangue , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/farmacologia , Benzamidas/sangue , Benzamidas/farmacocinética , Benzamidas/farmacologia , Linhagem Celular Tumoral , Colágeno , Citocinas/sangue , Cães , Feminino , Células HeLa , Humanos , Indazóis/sangue , Indazóis/farmacocinética , Indazóis/farmacologia , Insulina , Lipopolissacarídeos , Masculino , Metilprednisolona/farmacologia , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-Dawley
8.
Drug Metab Dispos ; 41(4): 814-26, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23355637

RESUMO

The natural product fumagillin exhibits potent antiproliferative and antiangiogenic properties. The semisynthetic analog PPI-2458, [(3R,4S,5S,6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methylbut-2-enyl)oxiran-2-yl]-1-oxaspiro[2.5]octan-6-yl] N-[(2R)-1-amino-3-methyl-1-oxobutan-2-yl]carbamate, demonstrates rapid inactivation of its molecular target, methionine aminopeptidase-2 (MetAP2), and good efficacy in several rodent models of cancer and inflammation with oral dosing despite low apparent oral bioavailability. To probe the basis of its in vivo efficacy, the metabolism of PPI-2458 was studied in detail. Reaction phenotyping identified CYP3A4/5 as the major source of metabolism in humans. Six metabolites were isolated from liver microsomes and characterized by mass spectrometry and nuclear resonance spectroscopy, and their structures were confirmed by chemical synthesis. The synthetic metabolites showed correlated inhibition of MetAP2 enzymatic activity and vascular endothelial cell growth. In an ex vivo experiment, MetAP2 inhibition in white blood cells, thymus, and lymph nodes in rats after single dosing with PPI-2458 and the isolated metabolites was found to correlate with the in vitro activity of the individual species. In a phase 1 clinical study, PPI-2458 was administered to patients with non-Hodgkin lymphoma. At 15 mg administered orally every other day, MetAP2 in whole blood was 80% inactivated for up to 48 hours, although the exposure of the parent compound was only ∼10% that of the summed cytochrome P450 metabolites. Taken together, the data confirm the participation of active metabolites in the in vivo efficacy of PPI-2458. The structures define a metabolic pathway for PPI-2458 that is distinct from that of TNP-470 ([(3R,4S,5S,6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methylbut-2-enyl)oxiran-2-yl]-1-oxaspiro[2.5]octan-6-yl] N-(2-chloroacetyl)carbamate). The high level of MetAP2 inhibition achieved in vivo supports the value of fumagillin-derived therapeutics for angiogenic diseases.


Assuntos
Aminopeptidases/antagonistas & inibidores , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/farmacocinética , Compostos de Epóxi/farmacocinética , Metaloendopeptidases/antagonistas & inibidores , Valina/análogos & derivados , Aminopeptidases/sangue , Animais , Esquema de Medicação , Compostos de Epóxi/administração & dosagem , Compostos de Epóxi/análise , Compostos de Epóxi/farmacologia , Humanos , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Linfonodos/efeitos dos fármacos , Linfonodos/metabolismo , Linfoma não Hodgkin/sangue , Linfoma não Hodgkin/tratamento farmacológico , Metaloendopeptidases/sangue , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Ratos , Relação Estrutura-Atividade , Timo/efeitos dos fármacos , Timo/metabolismo , Valina/administração & dosagem , Valina/análise , Valina/farmacocinética , Valina/farmacologia
9.
ACS Med Chem Lett ; 4(4): 381-6, 2013 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-24900682

RESUMO

Semisynthetic analogues of fumagillin, 1, inhibit methionine aminopeptidase-2 (MetAP2) and have entered the clinic for the treatment of cancer. An optimized fumagillin analogue, 3 (PPI-2458), was found to be orally active, despite containing a spiroepoxide function that formed a covalent linkage to the target protein. In aqueous acid, 3 underwent ring-opening addition of water and HCl, leading to four products, 4-7, which were characterized in detail. The chlorohydrin, but not the diol, products inhibited MetAP2 under weakly basic conditions, suggesting reversion to epoxide as a step in the mechanism. In agreement, chlorohydrin 6 was shown to revert rapidly to 3 in rat plasma. In an ex vivo assay, rats treated with purified acid degradants demonstrated inhibition of MetAP2 that correlated with the biochemical activity of the compounds. Taken together, the results indicate that degradation of the parent compound was compensated by the formation of active equivalents leading to a pharmacologically useful level of MetAP2 inhibition.

10.
ACS Med Chem Lett ; 3(12): 1070-4, 2012 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-24900430

RESUMO

Selective activation of the M1 muscarinic receptor via positive allosteric modulation represents an approach to treat the cognitive decline in patients with Alzheimer's disease. A series of amides were examined as a replacement for the carboxylic acid moiety in a class of quinolizidinone carboxylic acid M1 muscarinic receptor positive allosteric modulators, and leading pyran 4o and cyclohexane 5c were found to possess good potency and in vivo efficacy.

11.
Bioorg Med Chem ; 19(24): 7374-86, 2011 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-22079253

RESUMO

A series of partial agonists of the Glucocorticoid Receptor were prepared targeting reduced transactivation activity, while maintaining significant transrepression activity. Incorporation of an ortho-aryl amide produced compounds with the desired in vitro profile. Bioreactors consisting of Suspension cultures of Sf21 cells co expressing a CYP3A4 and NADPH-cytochrome P450 oxireductase were used to prepare the major metabolites of these compounds and revealed that oxidative N-dealkylation provided a pathway for formation of metabolites that were more agonistic than the parent partial agonists. Oxidative N-dealkylation was blocked in a new series of compounds, however oxidation alone was capable of producing full agonist metabolites. Incorporation of an ortho-primary amide and utilization of fluorine to modulate agonism afforded partial agonist MK-5932. Synthesis of the major metabolites of MK-5932 using bioreactor technology revealed that no significant GR-active metabolites were formed. Orally administered MK-5932 displayed anti-inflammatory efficacy in a Rat Oxazolone-induced chronic dermatitis model, while sparing plasma insulin.


Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Reatores Biológicos , Receptores de Glucocorticoides/agonistas , Animais , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Linhagem Celular , Citocromo P-450 CYP3A/metabolismo , Remoção de Radical Alquila , Dermatite/tratamento farmacológico , Feminino , Glucocorticoides/metabolismo , Humanos , Insetos , NADPH-Ferri-Hemoproteína Redutase/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Glucocorticoides/metabolismo
12.
J Med Chem ; 54(13): 4773-80, 2011 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-21682298

RESUMO

One approach to ameliorate the cognitive decline in Alzheimer's disease (AD) has been to restore neuronal signaling from the basal forebrain cholinergic system via the activation of the M(1) muscarinic receptor. A number of nonselective M(1) muscarinic agonists have previously shown positive effects on cognitive behaviors in AD patients, but were limited due to cholinergic adverse events thought to be mediated by the activation of the M(2) to M(5) subtypes. One strategy to confer selectivity for M(1) is the identification of positive allosteric modulators, which would target an allosteric site on the M(1) receptor rather than the highly conserved orthosteric acetylcholine binding site. Quinoline carboxylic acids have been previously identified as highly selective M(1) positive allosteric modulators with good pharmacokinetic and in vivo properties. Herein is described the optimization of a novel quinolizidinone carboxylic acid scaffold with 4-cyanopiperidines being a key discovery in terms of enhanced activity. In particular, modulator 4i gave high plasma free fractions, enhanced central nervous system (CNS) exposure, was efficacious in a rodent in vivo model of cognition, and afforded good physicochemical properties suitable for further preclinical evaluation.


Assuntos
Colinérgicos/síntese química , Nitrilas/síntese química , Nootrópicos/síntese química , Piperidinas/síntese química , Quinolizidinas/síntese química , Quinolizinas/síntese química , Receptor Muscarínico M1/fisiologia , Regulação Alostérica , Animais , Disponibilidade Biológica , Células CHO , Colinérgicos/química , Colinérgicos/farmacologia , Cricetinae , Cricetulus , Medo/efeitos dos fármacos , Humanos , Masculino , Camundongos , Nitrilas/química , Nitrilas/farmacologia , Nootrópicos/química , Nootrópicos/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Quinolizidinas/química , Quinolizidinas/farmacologia , Quinolizinas/química , Quinolizinas/farmacologia , Relação Estrutura-Atividade
13.
Bioorg Med Chem Lett ; 21(6): 1710-5, 2011 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-21324684

RESUMO

SAR study of the piperidine moiety in a series of quinolizidinone carboxylic acid M(1) positive allosteric modulators was examined. While the SAR was generally flat, compounds were identified with high CNS exposure to warrant additional in vivo evaluation.


Assuntos
Piperidinas/farmacologia , Regulação Alostérica , Animais , Células CHO , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Piperidinas/metabolismo , Relação Estrutura-Atividade
18.
ACS Med Chem Lett ; 1(6): 263-7, 2010 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-24900206

RESUMO

Positive allosteric modulation of the M1 muscarinic receptor represents an approach to treat the cognitive decline in patients with Alzheimer's disease. Replacement of a quinolone ring system in a quinolone carboxylic acid series of M1 modulators with a quinolizidinone bearing a basic amine linkage led to a series of compounds with higher free fraction, enhanced CNS exposure, and improved efficacy in rodent in vivo models of cognition.

19.
J Med Chem ; 52(24): 8047-56, 2009 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-19929003

RESUMO

Inhibition of methionine aminopeptidase-2 (MetAP2) represents a novel approach to antiangiogenic therapy. We describe the synthesis and activity of fumagillin analogues that address the pharmacokinetic and safety liabilities of earlier candidates in this compound class. Two-step elaboration of fumagillol with amines yielded a diverse series of carbamates at C6 of the cyclohexane spiroepoxide. The most potent of these compounds exhibited subnanomolar inhibition of cell proliferation in HUVEC and BAEC assays. Although a range of functionalities were tolerated at this position, alpha-trisubstituted amines possessed markedly decreased inhibitory activity, and this could be rationalized by modeling based on the known fumagillin-MetAP2 crystal structure. The lead compound resulting from these studies, (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-enyl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl (R)-1-amino-3-methyl-1-oxobutan-2-ylcarbamate, (PPI-2458), demonstrated an improved pharmacokinetic profile relative to the earlier clinical candidate TNP-470, and has advanced into phase I clinical studies in non-Hodgkin's lymphoma and solid cancers.


Assuntos
Aminopeptidases/antagonistas & inibidores , Carbamatos/química , Carbamatos/farmacologia , Cicloexanos/química , Cicloexanos/farmacologia , Ácidos Graxos Insaturados/química , Ácidos Graxos Insaturados/farmacologia , Metaloendopeptidases/antagonistas & inibidores , Aminoácidos/química , Animais , Bovinos , Processos de Crescimento Celular/efeitos dos fármacos , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Humanos , Modelos Moleculares , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Relação Estrutura-Atividade
20.
Clin Cancer Res ; 12(8): 2583-90, 2006 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-16638869

RESUMO

PURPOSE: Fumagillin and related compounds have potent antiproliferative activity through inhibition of methionine aminopeptidase-2 (MetAP-2). It has recently been reported that MetAP-2 is highly expressed in germinal center B cells and germinal center-derived non-Hodgkin's lymphomas (NHL), suggesting an important role for MetAP-2 in proliferating B cells. Therefore, we determined the importance of MetAP-2 in normal and transformed germinal center B cells by evaluating the effects of MetAP-2 inhibition on the form and function of germinal centers and germinal center-derived NHL cells. EXPERIMENTAL DESIGN: To examine the activity of PPI-2458 on germinal center morphology, spleen sections from cynomolgus monkeys treated with oral PPI-2458 were analyzed. Antiproliferative activity of PPI-2458 was assessed on germinal center-derived NHL lines in culture. A MetAP-2 pharmacodynamic assay was used to determine cellular MetAP-2 inhibition following PPI-2458 treatment. Finally, inhibition of MetAP-2 and proliferation by PPI-2458 was examined in the human SR NHL line in culture and in implanted xenografts. RESULTS: Oral PPI-2458 caused a reduction in germinal center size and number in lymphoid tissues from treated animals. PPI-2458 potently inhibited growth (GI(50) = 0.2-1.9 nmol/L) of several NHL lines in a manner that correlated with MetAP-2 inhibition. Moreover, orally administered PPI-2458 significantly inhibited SR tumor growth, which correlated with inhibition of tumor MetAP-2 (>85% at 100 mg/kg) in mice. CONCLUSIONS: These results show the potent antiproliferative activity of PPI-2458 on NHL lines in vitro and oral antitumor activity in vivo and suggest the therapeutic potential of PPI-2458 as a novel agent for treatment of NHL should be evaluated in the clinical setting.


Assuntos
Aminopeptidases/antagonistas & inibidores , Proliferação de Células/efeitos dos fármacos , Compostos de Epóxi/farmacologia , Linfoma não Hodgkin/tratamento farmacológico , Metaloendopeptidases/antagonistas & inibidores , Valina/análogos & derivados , Aminopeptidases/metabolismo , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos B/patologia , Western Blotting , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Compostos de Epóxi/uso terapêutico , Feminino , Centro Germinativo/efeitos dos fármacos , Centro Germinativo/patologia , Humanos , Contagem de Linfócitos , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Linfoma não Hodgkin/metabolismo , Linfoma não Hodgkin/patologia , Macaca fascicularis , Metaloendopeptidases/metabolismo , Camundongos , Camundongos SCID , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Fatores de Tempo , Valina/farmacologia , Valina/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
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