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1.
Drug Metab Dispos ; 46(7): 943-952, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29695616

RESUMO

To predict the impact of liver cirrhosis on hepatic drug clearance using physiologically based pharmacokinetic (PBPK) modeling, we compared the protein abundance of various phase 1 and phase 2 drug-metabolizing enzymes (DMEs) in S9 fractions of alcoholic (n = 27) or hepatitis C (HCV, n = 30) cirrhotic versus noncirrhotic (control) livers (n = 25). The S9 total protein content was significantly lower in alcoholic or HCV cirrhotic versus control livers (i.e., 38.3 ± 8.3, 32.3 ± 12.8, vs. 51.1 ± 20.7 mg/g liver, respectively). In general, alcoholic cirrhosis was associated with a larger decrease in the DME abundance than HCV cirrhosis; however, only the abundance of UGT1A4, alcohol dehydrogenase (ADH)1A, and ADH1B was significantly lower in alcoholic versus HCV cirrhotic livers. When normalized to per gram of tissue, the abundance of nine DMEs (UGT1A6, UGT1A4, CYP3A4, UGT2B7, CYP1A2, ADH1A, ADH1B, aldehyde oxidase (AOX)1, and carboxylesterase (CES)1) in alcoholic cirrhosis and five DMEs (UGT1A6, UGT1A4, CYP3A4, UGT2B7, and CYP1A2) in HCV cirrhosis was <25% of that in control livers. The abundance of most DMEs in cirrhotic livers was 25% to 50% of control livers. CES2 abundance was not affected by cirrhosis. Integration of UGT2B7 abundance in cirrhotic livers into the liver cirrhosis (Child Pugh C) model of Simcyp improved the prediction of zidovudine and morphine PK in subjects with Child Pugh C liver cirrhosis. These data demonstrate that protein abundance data, combined with PBPK modeling and simulation, can be a powerful tool to predict drug disposition in special populations.


Assuntos
Hepatite C/metabolismo , Inativação Metabólica/fisiologia , Cirrose Hepática Alcoólica/metabolismo , Cirrose Hepática/metabolismo , Fígado/metabolismo , Adulto , Idoso , Álcool Desidrogenase/metabolismo , Alcoólicos , Carboxilesterase/metabolismo , Citocromo P-450 CYP1A2/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Morfina/farmacocinética , Proteômica/métodos , Adulto Jovem , Zidovudina/farmacocinética
2.
Br J Clin Pharmacol ; 84(6): 1335-1345, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29469197

RESUMO

AIMS: Previous studies demonstrated direct correlation between CYP2C19 genotype and BMS-823778 clearance in healthy volunteers. The objective of the present study was to develop a physiologically-based pharmacokinetic (PBPK) model for BMS-823778 and use the model to predict PK and drug-drug interaction (DDI) in virtual populations with multiple polymorphic genes. METHODS: The PBPK model was built and verified using existing clinical data. The verified model was simulated to predict PK of BMS-823778 and significance of DDI with a strong CYP3A4 inhibitor in subjects with various CYP2C19 and UGT1A4 genotypes. RESULTS: The verified PBPK model of BMS-823778 accurately recovered observed PK in different populations. In addition, the model was able to capture the exposure differences between subjects with different CYP2C19 genotypes. PK simulation indicated higher exposures of BMS-823778 in CYP2C19 poor metabolizers who were also devoid of UGT1A4 activity, compared to those with normal UGT1A4 functionality. Moderate DDI with itraconazole was predicted in subjects with wild-type CYP2C19 or UGT1A4. However, in subjects without CYP2C19 or UGT1A4 functionality, significant DDI was predicted when BMS-823778 was coadministered with itraconazole. CONCLUSIONS: A PBPK model was developed using clinical data that accurately predicted human PK in different population with various CYP2C19 phenotypes. Simulations with the verified PBPK model indicated that UGT1A4 was probably an important clearance pathway in CYP2C19 poor metabolizers. DDI with itraconazole is likely to be dependent on the genotypes of CYP2C19 and UGT1A4.

3.
Int J Toxicol ; : 1091581816683642, 2017 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-28056568

RESUMO

BMS-986094, a 2'-C-methylguanosine prodrug for the treatment of chronic hepatitis C virus infection, was withdrawn from phase 2 clinical trials because of unexpected cardiac and renal toxicities. To better understand these toxicities, the in vitro metabolism of BMS-986094 in human hepatocytes (HHs) and human cardiomyocytes (HCMs) and the measurement of BMS-986094 and selected metabolites in monkey plasma and tissues were assessed. BMS-986094 was extensively metabolized by HHs and HCMs, resulting in more efficient formation and accumulation of the active triphosphorylated metabolite, INX-09114, and less efficient efflux of metabolites in HCMs. The predominant metabolism pathway (hydrolysis) in HHs and HCMs was not associated with the formation of reactive metabolites or oxidative stress. In cynomolgus monkeys dosed with BMS-986094 of 15 or 30 mg/kg/d for 3 weeks, the nucleoside metabolite M2 was the major plasma analyte (66%-68% of the combined area under the curve). INX-09114 was the highest drug-related species in the heart and kidney (2,610-4,280 ng/mL [males]; ∼2-420× the concentration of other analytes). Other analytes increased dose dependently, with BMS-986094 highest in diaphragm (≤4,400 ng/mL) followed by M2 in liver and kidney (≤1,360 ng/mL), and M7 and M8 in other tissues (≤124 ng/mL). Three weeks after the last dose, INX-09114 remained high in the heart and kidney (≤1,870 ng/mL), with low M2 (≤37 ng/mL) in plasma and tissues. Persistent high concentrations of INX-09114 in the heart and kidney appeared to correlate with toxicities in these tissues in monkeys.

4.
J Pharmacol Exp Ther ; 358(3): 397-404, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27317801

RESUMO

In the present study, an open-label, three-treatment, three-period clinical study of rosuvastatin (RSV) and rifampicin (RIF) when administered alone and in combination was conducted in 12 male healthy subjects to determine if coproporphyrin I (CP-I) and coproporphyrin III (CP-III) could serve as clinical biomarkers for organic anion transporting polypeptide 1B1 (OATP1B1) and 1B3 that belong to the solute carrier organic anion gene subfamily. Genotyping of the human OATP1B1 gene was performed in all 12 subjects and confirmed absence of OATP1B1*5 and OATP1B1*15 mutations. Average plasma concentrations of CP-I and CP-III prior to drug administration were 0.91 ± 0.21 and 0.15 ± 0.04 nM, respectively, with minimum fluctuation over the three periods. CP-I was passively eliminated, whereas CP-III was actively secreted from urine. Administration of RSV caused no significant changes in the plasma and urinary profiles of CP-I and CP-III. RIF markedly increased the maximum plasma concentration (Cmax) of CP-I and CP-III by 5.7- and 5.4-fold (RIF) or 5.7- and 6.5-fold (RIF+RSV), respectively, as compared with the predose values. The area under the plasma concentration curves from time 0 to 24 h (AUC0-24h) of CP-I and CP-III with RIF and RSV increased by 4.0- and 3.3-fold, respectively, when compared with RSV alone. In agreement with this finding, Cmax and AUC0-24h of RSV increased by 13.2- and 5.0-fold, respectively, when RIF was coadministered. Collectively, we conclude that CP-I and CP-III in plasma and urine can be appropriate endogenous biomarkers specifically and reliably reflecting OATP inhibition, and thus the measurement of these molecules can serve as a useful tool to assess OATP drug-drug interaction liabilities in early clinical studies.


Assuntos
Coproporfirinas/sangue , Coproporfirinas/urina , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Rifampina/farmacologia , Rosuvastatina Cálcica/farmacologia , Adulto , Biomarcadores/sangue , Biomarcadores/urina , Interações de Medicamentos , Humanos , Masculino , Pessoa de Meia-Idade , Rifampina/farmacocinética , Rosuvastatina Cálcica/farmacocinética , Adulto Jovem
5.
Bioanalysis ; 4(14): 1747-61, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22877221

RESUMO

BACKGROUND: An integrated method that provides rates of both parent disappearance and metabolite formation was developed. RESULTS: Buspirone, mirtazapine and verapamil were used as model compounds in developing the method. Incubations were carried out on a robotic platform. Qualitative analysis of metabolites in 30 µM samples was conducted by data-dependent HPLC-MS/MS on a high-resolution instrument. Quantitative analysis of the parent compound and metabolites in 0.5 µM samples was conducted by full-scan MS(2) with product ion extraction using an ion trap mass spectrometer. Data generated for the compounds included half-life and intrinsic clearance of the parent molecule, characterization of metabolites and relative rates of metabolite formation. A correction factor was used to convert MS responses of metabolites in 0.5 µM samples to UV areas in order to compare relative metabolite concentrations. CONCLUSION: The approach allows for the investigation of a set of six compounds simultaneously, with a turnaround time of 1 week or less.


Assuntos
Técnicas de Química Analítica , Avaliação Pré-Clínica de Medicamentos/métodos , Farmacocinética , Animais , Automação , Biotransformação , Buspirona/análise , Buspirona/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Cães , Meia-Vida , Humanos , Mianserina/análogos & derivados , Mianserina/análise , Mianserina/farmacocinética , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Mirtazapina , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem/métodos , Verapamil/análise , Verapamil/farmacocinética
6.
Artigo em Inglês | MEDLINE | ID: mdl-22349123

RESUMO

A liquid chromatography and tandem mass spectrometry (LC-MS/MS) method was developed and validated to simultaneously determine the concentrations of saxagliptin (Onglyza™, BMS-477118) and its major active metabolite, 5-hydroxy saxagliptin to support pharmacokinetic analyses in clinical studies. The dynamic range of the assay was 0.1-50 ng/mL for saxagliptin and 0.2-100 ng/mL for 5-hydroxy saxagliptin. Protein precipitation (PPT) with acetonitrile was used to extract the analytes from plasma matrix before injecting on an Atlantis(®) dC18 column (50 mm × 2.1 mm, 5 µm) for LC-MS/MS analysis. The sample pre-treatment process was carefully controlled to disrupt DPP4-specific binding and non-specific binding observed at lower concentrations. The recoveries for both analytes were >90%. The assay was selective, rugged and reproducible; storage stability of at least 401 days at -20°C was demonstrated. Under these chromatographic conditions, the isomers of saxagliptin and 5-hydroxy saxagliptin were chromatographically separated from saxagliptin and 5-hydroxy saxagliptin. The assay has been used to support multiple clinical studies and regulatory approvals.


Assuntos
Adamantano/análogos & derivados , Cromatografia Líquida/métodos , Dipeptídeos/sangue , Espectrometria de Massas em Tandem/métodos , Adamantano/sangue , Adamantano/química , Adamantano/farmacocinética , Dipeptídeos/química , Dipeptídeos/farmacocinética , Estabilidade de Medicamentos , Humanos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Estereoisomerismo
7.
Drug Metab Dispos ; 38(11): 2049-59, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20668249

RESUMO

(3R,4R)-4-Amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)-3-piperidinol (BMS-690514), an oral selective inhibitor of human epidermal growth factor receptors 1 (or epidermal growth factor receptor), 2, and 4, and vascular endothelial growth factor receptors 1, 2, and 3, is being developed as a treatment for patients with non-small-cell lung cancer and metastatic breast cancer. The disposition of [(14)C]BMS-690514 was investigated in nine healthy male subjects (group 1, n = 6; group 2, n = 3) after oral administration of a 200-mg dose. Urine, feces, and plasma were collected from all subjects for up to 12 days postdose. In group 2 subjects, bile was collected from 3 to 8 h postdose. Across groups, approximately 50 and 34% of administered radioactivity was recovered in the feces and urine, respectively. An additional 16% was recovered in the bile of group 2 subjects. Less than 28% of the dose was recovered as parent drug in the combined excreta, suggesting that BMS-690514 was highly metabolized. BMS-690514 was rapidly absorbed (median time of maximum observed concentration 0.5 h) with the absorbed fraction estimated to be approximately 50 to 68%. BMS-690514 represented ≤7.9% of the area under the concentration-time curve from time 0 extrapolated to infinite time of plasma radioactivity, indicating that the majority of the circulating radioactivity was from metabolites. BMS-690514 was metabolized via multiple oxidation reactions and direct glucuronidation. Circulating metabolites included a hydroxylated rearrangement product (M1), a direct ether glucuronide (M6), and multiple secondary glucuronide conjugates. None of these metabolites is expected to contribute to the pharmacology of BMS-690514. In summary, BMS-690514 was well absorbed and extensively metabolized via multiple metabolic pathways in humans, with excretion of drug-related radioactivity in both bile and urine.


Assuntos
Antineoplásicos/farmacocinética , Piperidinas/farmacocinética , Pirróis/farmacocinética , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Triazinas/farmacocinética , Absorção , Administração Oral , Adolescente , Adulto , Antineoplásicos/sangue , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/urina , Bile/química , Biotransformação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Relação Dose-Resposta a Droga , Fezes/química , Glucuronídeos/metabolismo , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Humanos , Hidroxilação , Masculino , Oxirredução , Piperidinas/sangue , Piperidinas/metabolismo , Piperidinas/farmacologia , Piperidinas/urina , Polimorfismo de Nucleotídeo Único , Proteínas Quinases/metabolismo , Pirróis/sangue , Pirróis/metabolismo , Pirróis/farmacologia , Pirróis/urina , Distribuição Tecidual , Triazinas/sangue , Triazinas/metabolismo , Triazinas/farmacologia , Triazinas/urina , Adulto Jovem
8.
Anal Chem ; 81(7): 2695-700, 2009 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-19254033

RESUMO

Nonselective collision-induced dissociation (CID) is a technique for producing fragmentation products for all ions generated in an ion source. It is typical of liquid chromatography/mass spectrometry (LC/MS) analysis of complex samples that matrix-related components may contribute to the resulting product ion spectra and confound the usefulness of this technique for structure interpretation. In this proof-of-principle study, a high-resolution LC/MS-based background subtraction algorithm was used to process the nonselective CID data to obtain clean product ion spectra for metabolites in human plasma samples. With buspirone and clozapine metabolites in human plasma as examples, this approach allowed for not only facile detection of metabolites of interest but also generation of their respective product ion spectra that were clean and free of matrix-related interferences. This was demonstrated with both an MS(E) technique (where E represents collision energy) with a quadrupole time-of-flight (QTOF) instrument and an in-source fragmentation technique with an LTQ Orbitrap instrument. The combined nonselective CID and background subtraction approach should allow for detection and structural interpretation of other types of sample analyses where control samples are obtained.


Assuntos
Algoritmos , Cromatografia Líquida/métodos , Espectrometria de Massas/métodos , Artefatos , Humanos , Preparações Farmacêuticas/sangue , Preparações Farmacêuticas/química , Técnica de Subtração
9.
Drug Metab Dispos ; 36(12): 2564-70, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18787054

RESUMO

Dasatinib [N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide; BMS-354825] is a potent and broad-spectrum kinase inhibitor used for the treatment of chronic myeloid leukemia and Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia. Dasatinib exhibited extensive lacteal secretion in Sprague-Dawley rats following a single p.o. dose of [14C]dasatinib (10 mg/kg, 300 microCi/kg). Radioactivity was detected through 72 h postdose, with a milk/plasma area under concentration-time curve from 0 to infinity (AUC(0-inf)) ratio of approximately 25. The majority of the total radioactivity in milk was attributed to unchanged dasatinib. After a single dose of [14C]dasatinib to pregnant Sprague-Dawley rats at gestation day 18, radioactivity was extensively distributed in maternal tissues. The radioactivity detected by tissue excision or quantitative whole-body autoradiography was highest in adrenal gland, mammary tissue, lungs, kidneys, liver, and placenta. Compared with maternal tissues, a relatively low level of radioactivity was detected in fetal tissues. The concentrations of dasatinib-equivalents in fetal liver and kidneys were <13% of the respective maternal organs. The C(max) of dasatinib-equivalents in fetal blood was approximately 39% of that in maternal blood; however, the AUC values were comparable. Fetal brain/blood ratios of C(max) and AUC(0-inf) were approximately 1.58 and 1.48, respectively, which were much greater than the maternal ratios of 0.12 and 0.13. In summary, dasatinib was extensively distributed in maternal tissues and secreted into milk, but its penetration into the adult brain was limited. Transporters may be involved in mediating dasatinib distribution in the adult rat, whereas in the fetus, tissue and blood exposures were similar, suggesting that distribution in the fetus is predominantly mediated by diffusion.


Assuntos
Feto/metabolismo , Leite/metabolismo , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Tiazóis/metabolismo , Tiazóis/farmacocinética , Animais , Área Sob a Curva , Autorradiografia , Dasatinibe , Feminino , Feto/química , Leite/química , Estrutura Molecular , Gravidez , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/sangue , Ratos , Ratos Sprague-Dawley , Tiazóis/sangue , Distribuição Tecidual
10.
Bioorg Med Chem Lett ; 18(17): 4770-3, 2008 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-18707880

RESUMO

Inhibition of sodium-dependent glucose transporter 2 (SGLT2), the transporter that is responsible for renal re-uptake of glucose, leads to glucosuria in animals. SGLT-mediated glucosuria provides a mechanism to shed excess plasma glucose to ameliorate diabetes-related hyperglycemia and associated complications. The current study demonstrates that the proper relationship of a 4'-substituted benzyl group to a beta-1C-phenylglucoside is important for potent and selective SGLT2 inhibition. The lead C-arylglucoside (7a) demonstrates superior metabolic stability to its O-arylglucoside counterpart (4) and it promotes glucosuria when administered in vivo.


Assuntos
Glucosídeos/química , Glucosídeos/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Glucose/química , Glicosúria Renal/tratamento farmacológico , Humanos , Rim/efeitos dos fármacos , Ratos , Transportador 1 de Glucose-Sódio/antagonistas & inibidores
11.
Bioorg Med Chem Lett ; 18(14): 4072-4, 2008 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-18554903

RESUMO

The first enantioselective synthesis of (D)-2-tert-butoxycarbonylamino-5,5-difluoro-5-phenyl-pentanoic acid 3 was achieved. The incorporation of the titled compound into growth hormone secretagogue (GHS) compounds resulted in new analogs 10 and 16, both of which had significantly increased in vitro potency. The compound 10 also showed improved in vivo efficacy as well as pharmacokinetic properties in rat models.


Assuntos
Hormônio do Crescimento/metabolismo , Ácidos Pentanoicos/síntese química , Administração Oral , Animais , Área Sob a Curva , Disponibilidade Biológica , Carbamatos/farmacologia , Química Farmacêutica/métodos , Desenho de Drogas , Indóis/farmacologia , Modelos Químicos , Ácidos Pentanoicos/química , Ácidos Pentanoicos/farmacologia , Hormônios Peptídicos/química , Ratos , Compostos de Espiro/farmacologia , Estereoisomerismo , Tetrazóis/farmacologia
12.
J Med Chem ; 51(5): 1145-9, 2008 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-18260618

RESUMO

The C-aryl glucoside 6 (dapagliflozin) was identified as a potent and selective hSGLT2 inhibitor which reduced blood glucose levels in a dose-dependent manner by as much as 55% in hyperglycemic streptozotocin (STZ) rats. These findings, combined with a favorable ADME profile, have prompted clinical evaluation of dapagliflozin for the treatment of type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/síntese química , Hipoglicemiantes/síntese química , Rim/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose , Administração Oral , Animais , Compostos Benzidrílicos , Glicemia/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Glucosídeos/química , Glucosídeos/farmacologia , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Ratos , Estereoisomerismo
13.
Bioorg Med Chem Lett ; 18(6): 1825-9, 2008 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-18295486

RESUMO

The structure-activity relationship of the O-benzyl serine side chain was investigated based on the tetrazole-based growth hormone secretagogue BMS-317180 (2). The ortho position of the benzyl moiety was found to be favorable for introduction of substituents. A series of ortho-substituted compounds were synthesized with improved in-vitro and in-vivo activity. Among them, the biphenyl compound 2p shows twofold improvement in potency compared to its parent compound BMS-317180 (2).


Assuntos
Desenho de Drogas , Hormônio do Crescimento/metabolismo , Serina/análogos & derivados , Tetrazóis/química , Tetrazóis/farmacologia , Animais , Carbamatos/farmacologia , Estrutura Molecular , Ratos , Serina/química , Relação Estrutura-Atividade , Tetrazóis/síntese química
14.
J Med Chem ; 50(24): 5890-3, 2007 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-17973363

RESUMO

A tetrazole-based peptidomimetic 2 (BMS-317180) was discovered as a human growth hormone secretagogue (GHS). Compound 2 is a potent, novel, orally effective GHS that shows an excellent safety profile in preclinical studies. The compound was advanced into clinical development.


Assuntos
Carbamatos/síntese química , Hormônio do Crescimento/metabolismo , Tetrazóis/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Carbamatos/farmacocinética , Carbamatos/farmacologia , Cães , Ésteres , Hormônio do Crescimento/sangue , Hormônio do Crescimento Humano/metabolismo , Humanos , Macaca fascicularis , Ratos , Solubilidade , Relação Estrutura-Atividade , Tetrazóis/farmacocinética , Tetrazóis/farmacologia , Água
15.
J Clin Nurs ; 12(6): 899-911, 2003 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-14632983

RESUMO

This study aimed to investigate the information provided to patients undergoing gastroscopy procedures in Northern Ireland. Questionnaires were developed by the authors and were completed by 402 patients (RR = 43.8%) and 62 nurses (RR = 75.6%). Patients received most of the procedural information from nurses, and they recognized the importance of providing sensory information. Patients were generally satisfied with the information provided. There is clear evidence of fragmented care, and major changes are required to ensure that patients receive holistic information that includes procedural and sensory aspects. Nurses and doctors must realize that their role in information giving is to ensure that comprehensive information is provided by the appropriate professional at the appropriate time.


Assuntos
Gastroscopia , Papel do Profissional de Enfermagem , Educação de Pacientes como Assunto , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Irlanda do Norte , Recursos Humanos de Enfermagem no Hospital , Satisfação do Paciente , Inquéritos e Questionários
16.
J Med Chem ; 45(18): 3905-27, 2002 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-12190313

RESUMO

High throughput screening identified 2-acetamido-thiazolylthio acetic ester 1 as an inhibitor of cyclin-dependent kinase 2 (CDK2). Because this compound is inactive in cells and unstable in plasma, we have stabilized it to metabolic hydrolysis by replacing the ester moiety with a 5-ethyl-substituted oxazole as in compound 14. Combinatorial and parallel synthesis provided a rapid analysis of the structure-activity relationship (SAR) for these inhibitors of CDK2, and over 100 analogues with IC(50) values in the 1-10 nM range were rapidly prepared. The X-ray crystallographic data of the inhibitors bound to the active site of CDK2 protein provided insight into the binding modes of these inhibitors, and the SAR of this series of analogues was rationalized. Many of these analogues displayed potent and broad spectrum antiproliferative activity across a panel of tumor cell lines in vitro. In addition, A2780 ovarian carcinoma cells undergo rapid apoptosis following exposure to CDK2 inhibitors of this class. Mechanism of action studies have confirmed that the phosphorylation of CDK2 substrates such as RB, histone H1, and DNA polymerase alpha (p70 subunit) is reduced in the presence of compound 14. Further optimization led to compounds such as water soluble 45, which possesses a favorable pharmacokinetic profile in mice and demonstrates significant antitumor activity in vivo in several murine and human models, including an engineered murine mammary tumor that overexpresses cyclin E, the coactivator of CDK2.


Assuntos
Antineoplásicos/síntese química , Benzenoacetamidas , CDC2-CDC28 Quinases , Quinases Ciclina-Dependentes/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Oxazóis/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Tiazóis/síntese química , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Técnicas de Química Combinatória , Cristalografia por Raios X , Ciclina E/metabolismo , Quinase 2 Dependente de Ciclina , DNA Polimerase I/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Feminino , Histonas/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , Modelos Moleculares , Oxazóis/farmacocinética , Oxazóis/farmacologia , Fosforilação , Ligação Proteica , Proteína do Retinoblastoma/metabolismo , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacocinética , Tiazóis/farmacologia , Células Tumorais Cultivadas
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