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J Org Chem ; 80(14): 7019-32, 2015 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-26151079


Clopidogrel is a prodrug anticoagulant with active metabolites that irreversibly inhibit the platelet surface GPCR P2Y12 and thus inhibit platelet activation. However, gaining an understanding of patient response has been limited due to imprecise understanding of metabolite activity and stereochemistry, and a lack of acceptable analytes for quantifying in vivo metabolite formation. Methods for the production of all bioactive metabolites of clopidogrel, their stereochemical assignment, and the development of stable analytes via three conceptually orthogonal routes are disclosed.

Microssomos Hepáticos/metabolismo , Piperidinas/síntese química , Inibidores da Agregação de Plaquetas/síntese química , Inibidores da Agregação de Plaquetas/metabolismo , Pró-Fármacos/síntese química , Ticlopidina/análogos & derivados , Fenômenos Biológicos , Clopidogrel , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Piperidinas/química , Inibidores da Agregação de Plaquetas/química , Pró-Fármacos/química , Estereoisomerismo , Ticlopidina/síntese química , Ticlopidina/química , Ticlopidina/metabolismo
Chem Res Toxicol ; 27(12): 2052-61, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25372409


Certain aromatic nitriles are well-known inhibitors of cysteine proteases. The mode of action of these compounds involves the formation of a reversible or irreversible covalent bond between the nitrile and a thiol group in the active site of the enzyme. However, the reactivity of these aromatic nitrile-substituted heterocycles may lead inadvertently to nonspecific interactions with DNA, protein, glutathione, and other endogenous components, resulting in toxicity and complicating the use of these compounds as therapeutic agents. In the present study, the intrinsic reactivity and associated structure-property relationships of cathepsin K inhibitors featuring substituted pyridazines [6-phenylpyridazine-3-carbonitrile, 6-(4-fluorophenyl)pyridazine-3-carbonitrile, 6-(4-methoxyphenyl)pyridazine-3-carbonitrile, 6-p-tolylpyridazine-3-carbonitrile], pyrimidines [5-p-tolylpyrimidine-2-carbonitrile, 5-(4-fluorophenyl)pyrimidine-2-carbonitrile], and pyridines [5-p-tolylpicolinonitrile and 5-(4-fluorophenyl)picolinonitrile] were evaluated using a combination of computational and analytical approaches to establish correlations between electrophilicity and levels of metabolites that were formed in glutathione- and N-acetylcysteine-supplemented human liver microsomes. Metabolites that were characterized in this study featured substituted thiazolines that were formed following rearrangements of transient glutathione and N-acetylcysteine conjugates. Peptidases including γ-glutamyltranspeptidase were shown to catalyze the formation of these products, which were formed to lesser extents in the presence of the selective γ-glutamyltranspeptidase inhibitor acivicin and the nonspecific peptidase inhibitors phenylmethylsulfonyl fluoride and aprotinin. Of the chemical series mentioned above, the pyrimidine series was the most susceptible to metabolism to thiazoline-containing products, followed, in order, by the pyridazine and pyridine series. This trend was in keeping with the diminishing electrophilicity across these series, as demonstrated by in silico modeling. Hence, mechanistic insights gained from this study could be used to assist a medicinal chemistry campaign to design cysteine protease inhibitors that were less prone to the formation of covalent adducts.

Microssomos Hepáticos/metabolismo , Modelos Químicos , Nitrilos/metabolismo , Piridazinas/metabolismo , Piridinas/metabolismo , Pirimidinas/metabolismo , Tiazóis/metabolismo , Cromatografia Líquida , Humanos , Espectroscopia de Ressonância Magnética , Espectrofotometria Ultravioleta , Espectrometria de Massas em Tandem