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Levesque J.F.,Merck Frosst Center for Therapeutic Research
Methods in molecular biology (Clifton, N.J.) | Year: 2011

Xenobiotics, including therapeutic agents, can produce a variety of beneficial, as well as adverse, effects in mammals. One potential source of drug-mediated toxicity stems from metabolic activation of the parent compound, typically catalyzed by one or more members of the cytochrome P450 family of enzymes. The resulting electrophile, if not quenched by low molecular weight endogenous nucleophiles, can form covalent adducts to cellular proteins, potentially resulting in enzyme inactivation, cell death, or formation of an immunogenic species. The toxicological consequences of exposure to such reactive intermediates range from mild inflammation to organ failure, anaphylaxis, and death. At Merck Research Laboratories, the potential of drug candidates to bind covalently to proteins is evaluated at the lead optimization stage of drug discovery by incubating a radiolabeled analog of the compound in question with liver microsomal preparations (under oxidative conditions) or whole cells (full cellular metabolic capability), typically derived from rat and human liver. A semi-automated method based on the Brandel Harvester technique then is used to measure the formation of covalent adducts of the test compound to liver proteins. This assay is viewed as an important component of drug discovery programs, since the findings are employed to guide specific efforts to abrogate bioactivation issues through informed structural modification of lead compounds. Source


Levesque P.,Merck Frosst Center for Therapeutic Research | Fournier P.-A.,Merck Frosst Center for Therapeutic Research
Journal of Organic Chemistry | Year: 2010

A mild, efficient, and simple method for the synthesis of 3-ethoxycarbonylindoles has been developed. Addition of ethyl diazoacetate (EDA) to 2-aminobenzaldehydes cleanly affords the indole core. As opposed to other common approaches for the synthesis of indole, this method displays both excellent functional group tolerance and perfect regiochemical control. This allowed the synthesis of a variety of useful indole building blocks from 2-aminobenzaldehydes derived from readily available anthranilic acids. © 2010 American Chemical Society. Source


Li L.,Merck Frosst Center for Therapeutic Research | Chua W.K.S.,Merck Frosst Center for Therapeutic Research
Tetrahedron Letters | Year: 2011

We have developed a robust approach for the synthesis of 3,4-fused isoquinolin-1(2H)-one analogs. A benzonitrile or a nicotinonitrile bearing an ortho-substituent, such as -OH, -SH, or -NHR (R = alkyl or aryl) can be deprotonated by KOtBu and then reacted with methyl 2-(bromomethyl)benzoate (8) to form its corresponding O-, S-, or N-alkylation product. The product thus formed is then treated with KOtBu again to initiate a cascade process that will lead to the formation of its corresponding 3,4-fused isoquinolin-1(2H)-one. This multistep synthesis as well as the final product purification is achieved in a one-pot manner. © 2011 Elsevier Ltd. All rights reserved. Source


Li L.,Merck Frosst Center for Therapeutic Research | Chua W.K.S.,Merck Frosst Center for Therapeutic Research
Tetrahedron Letters | Year: 2011

We have developed an efficient one-pot multistep sequence to the synthesis of 3-aminoindolizine derivatives by using Hantzsch ester (9) as a mild hydride transfer agent. The reaction scope was investigated and the effect of substrates on reaction outcomes was discussed. Source


Truong V.L.,Merck Frosst Center for Therapeutic Research | Morrow M.,Merck Frosst Center for Therapeutic Research
Tetrahedron Letters | Year: 2010

Condensation of o-iodobenzaldehydes 1a_c with amidine hydrochlorides 2a_p under ligand-free copper-catalyzed Ullmann N-arylation conditions afforded the corresponding quinazolines 3a-r in good to excellent yields. © 2009 Elsevier Ltd. All rights reserved. Source

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