Medicinal Chemistry of Drugs with Active Metabolites Following Conjugation

Kalász, Huba; Petroianu, Georg; Hosztafi, Sándor; Darvas, Ferenç; Csermely, Tamás; Adeghate, Ernest; Siddiq, Afshan; Tekes, Kornélia

doi:10.2174/1389557511313110002

Cited by 7 publications

(3 citation statements)

References 37 publications

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“…Identification of the structure of phase-I and phase-II metabolites and its quantity is essential to understand the elimination of drugs, metabolites and residence time of drugs, metabolites in human system. LC-MS/MS plays a crucial role in rapid identification of the metabolic soft spots and hot spots and directs synthetic chemists to make appropriate modifications in the drug moiety [43,44].…”

Section: Identification Of Metabolitesmentioning

confidence: 99%

In Vitro Biotransformation in Drug Discovery

Ravindran¹,

Rokade²,

Suthar³

et al. 2018

Drug Discovery - Concepts to Market

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In vitro Biotransformation studies play a crucial role in drug discovery program that determine the fate of the new chemical entities (NCE's). Enzyme rich matrices such as microsomes, hepatocytes, liver fractions and S9 fractions transform the new chemical entities to different metabolites. Metabolites could be pharmacologically important or toxic. Newly formed metabolites are identified using liquid chromatography interfaced with mass spectrometry. Identification of the biotransformation sites in the new chemical entity helps the medicinal chemists to optimize its structure and develop the NCE as a pharmaceutical drug. Screening pharmaceutical drugs using in vitro biotransformation studies assist in selecting the right new chemical entity for further in vivo studies in animal systems and later in human clinical trials.

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Section: Identification Of Metabolitesmentioning

confidence: 99%

In Vitro Biotransformation in Drug Discovery

Ravindran¹,

Rokade²,

Suthar³

et al. 2018

Drug Discovery - Concepts to Market

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“…The topic of xenobiotic phosphorylation has attracted more attention recently owing to intentionally designed kinase-substrate analogs that depend on kinase-catalyzed activation to form phosphorylated active drugs. Examples include a number of antiviral and anticancer drugs that are nucleoside mimetics requiring phosphorylation to activate, as well as the immunomodulatory drug fingolimod (Kalász et al, 2013;Mitchell, 2016). Fingolimod is a structural analog of sphingosine and is phosphorylated by sphingosine kinases to become an agonist of the sphingosine-1-phosphate receptor (Mandala et al, 2002;Billich et al, 2003;Zollinger et al, 2011;David et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Mouse Red Blood Cell–Mediated Rare Xenobiotic Phosphorylation of a Drug Molecule Not Intended to Be a Kinase Substrate

Wen

Doig

et al. 2017

Drug Metab Dispos

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Phosphorylation of xenobiotics is rare, probably owing to a strong evolutionary pressure against it. This rarity may have attracted more attention recently as a result of intentionally designed kinase-substrate analogs that depend on kinase-catalyzed activation to form phosphorylated active drugs. We report a rare phosphorylated metabolite observed unexpectedly in mouse plasma samples after an oral dose of a Tankyrase inhibitor that was not intended to be a kinase substrate, i.e., ()-2-(4-(6-(3,4-dimethylpiperazin-1-yl)-4-methylpyridin-3-yl)phenyl)-8-(hydroxymethyl)quinazolin-4(3)-one (AZ2381). The phosphorylated metabolite was not generated in mouse hepatocytes. In vitro experiments showed that the phosphorylation of AZ2381 occurred in mouse whole blood with heparin as anticoagulant but not in mouse plasma. The phosphorylated metabolite was also produced in rat, dog, and human blood, albeit at lower yields than in mouse. Divalent metal ions are required for the phosphorylation since the reaction is inhibited by the metal chelator EDTA. Further investigations with different cellular fractions of mouse blood revealed that the phosphorylation of AZ2381 was mediated by erythrocytes but did not occur with leukocytes. The levels of O incorporation into the phosphorylated metabolite when inorganicO-phosphate and -O-ATP were added to the mouse blood incubations separately suggested that the phosphoryl transfer was from inorganic phosphate rather than ATP. It remains unclear which enzyme present in red blood cells is responsible for this rare phosphorylation.

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“…However, some glucuronides (mostly O ‐acyl‐glucuronides such as diclofenac‐glucuronide) are held responsible for adverse drug reactions . On the other hand, some glucuronides, for example, morphine‐6‐glucuronide or ezetimibe‐glucuronide, exhibit biological effects that significantly contribute to the efficacy of the parent drugs . Together with the fact that glucuronidation can play a role in drug–drug interactions with clinical relevance, these findings led to an increased interest in pharmacokinetic data of drug glucuronides .…”

Section: Introductionmentioning

confidence: 99%