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1.
Chem Res Toxicol ; 26(6): 926-36, 2013 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-23721565

RESUMO

Sitaxentan is a selective endothelin-A receptor antagonist that was marketed as Thelin in several European countries and Canada for pulmonary arterial hypertension. Sitaxentan was undergoing further clinical trials in the United States but due to four deaths and one case of liver transplantation from severe liver toxicity that appeared to be idiosyncratic in nature, it was withdrawn worldwide in December, 2010. Sitaxentan contains a 1,3-benzodioxole ring that undergoes enzymatic demethyleneation to an ortho-catechol metabolite that can further oxidize to a reactive ortho-quinone metabolite. Here, we report the detection and mass spectral characterization of a glutathione conjugate of this sitaxentan quinone reactive metabolite that was trapped in vitro using mouse, rat, dog, and human liver microsomes supplemented with NADPH and glutathione and that was also observed in rat and human hepatocytes. Using human liver microsomes, we also demonstrated that P450 3A4 undergoes time-dependent inhibition. Density functional calculations on the catechol metabolite of sitaxentan indicated that the reaction leading to the quinone was thermodynamically favorable with an enthalpy change of -6.3 kcal/mol. Using density functional methodology, we modeled the attack of glutathione on the quinone with an S-methyl thiolate anion which allowed us to predict, based on the difference in transition state energies, that the 2-position on the phenyl ring was more likely than the 5-position as the site of glutathione conjugation. Overall, our results demonstrated that sitaxentan is capable of facile formation of a reactive ortho-quinone metabolite capable of reacting with glutathione and may rationalize the idiosyncratic nature of the hepatotoxicity that led to its withdrawal.


Assuntos
Inibidores das Enzimas do Citocromo P-450 , Sistema Enzimático do Citocromo P-450/metabolismo , Glutationa/química , Hepatócitos/metabolismo , Isoxazóis/metabolismo , Isoxazóis/toxicidade , Microssomos Hepáticos/metabolismo , Tiofenos/metabolismo , Tiofenos/toxicidade , Animais , Benzoquinonas/química , Benzoquinonas/metabolismo , Biotransformação , Catecóis/química , Catecóis/metabolismo , Cromatografia Líquida , Sistema Enzimático do Citocromo P-450/biossíntese , Cães , Humanos , Isoxazóis/efeitos adversos , Isoxazóis/química , Camundongos , Teoria Quântica , Ratos , Espectrometria de Massas em Tandem , Tiofenos/efeitos adversos , Tiofenos/química
2.
Bioorg Med Chem Lett ; 23(7): 1967-73, 2013 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-23454015

RESUMO

Leucine-rich repeat kinase 2 (LRRK2) has been implicated in the pathogenesis of Parkinson's disease (PD). Inhibition of LRRK2 kinase activity is a therapeutic approach that may lead to new treatments for PD. Herein we report the discovery of a series of [1,2,4]triazolo[4,3-b]pyridazines that are potent against both wild-type and mutant LRRK2 kinase activity in biochemical assays and show an unprecedented selectivity towards the G2019S mutant. A structural rational for the observed selectivity is proposed.


Assuntos
Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Piridazinas/farmacologia , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Piridazinas/síntese química , Piridazinas/química , Relação Estrutura-Atividade
3.
Bioorg Med Chem Lett ; 20(20): 6034-9, 2010 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-20822903
4.
Nat Biotechnol ; 34(3): 303-11, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26829319

RESUMO

Haplotyping of human chromosomes is a prerequisite for cataloguing the full repertoire of genetic variation. We present a microfluidics-based, linked-read sequencing technology that can phase and haplotype germline and cancer genomes using nanograms of input DNA. This high-throughput platform prepares barcoded libraries for short-read sequencing and computationally reconstructs long-range haplotype and structural variant information. We generate haplotype blocks in a nuclear trio that are concordant with expected inheritance patterns and phase a set of structural variants. We also resolve the structure of the EML4-ALK gene fusion in the NCI-H2228 cancer cell line using phased exome sequencing. Finally, we assign genetic aberrations to specific megabase-scale haplotypes generated from whole-genome sequencing of a primary colorectal adenocarcinoma. This approach resolves haplotype information using up to 100 times less genomic DNA than some methods and enables the accurate detection of structural variants.


Assuntos
Haplótipos/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias/genética , Análise de Sequência de DNA/métodos , DNA/genética , Genoma Humano , Variação Estrutural do Genoma , Células Germinativas , Humanos , Conformação de Ácido Nucleico , Proteínas de Fusão Oncogênica/genética , Polimorfismo de Nucleotídeo Único
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