Metabolically Stable tert-Butyl Replacement ACS Med Chem Lett 2013


Barnes-Seeman, D. et al. ACS Med. Chem. Lett., 2013, 4 (6), pp 514–516
Novartis Institutes for Biomedical Research

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Deuterated Clopidogrel Analogues as a New Generation of Antiplatelet Agents ACS Med Chem Lett 2013

Zhu, Y. et al. ACS Med. Chem. Lett., 2013, 4 (3), pp 349–352

Deuteration inhibited the P450-mediated metabolism on the piperidine ring and more oxidations occurred on the thiophene ring via bioactivation pathway, thereby improving the therapeutic effects.

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Thiolactone Sulfoxides as New Reactive Metabolites Acting as Bis-Electrophiles: Implication in Clopidogrel and Prasugrel Bioactivation CRT 2013

Dansette, P. M., et al. Chem. Res. Toxicol., Article ASAP

“Thiolactone sulfoxides are formed as reactive metabolites in the metabolism of clopidogrel and prasugrel and are able to react as bis-electrophiles with a variety of nucleophiles.”

Posted in Bioactivation, Biotransformation, Clopidogrel, Prasugrel, Reactive Intermediates | Tagged , , , | Leave a comment

Which Metabolites Circulate? Minireview DMD 2013



Loi, C. M., Smith, D. A., Dalvie, D. Drug Metab. Dispos. 2013 May;41(5):933-51.

“This review examines the abundance of metabolites relative to the total parent drug [metabolite-to-parent (M/P) ratio] from 125 drugs in relation to their structural and physicochemical characteristics, lipoidal permeability, protein binding, and fractional formation from parent (fm). Our analysis suggests that fm is the major determinant of total drug M/P ratio for amine, alcohol, N- and S-oxide, and carboxylic acid metabolites.”

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Boronic Acid-Containing Proteasome Inhibitors: Alert to Potential Pharmaceutical Bioactivation CRT 2013

Boronic acid
Li. A. C. et al. Chem. Res. Toxicol., 2013, 26 (4), pp 608–615

Posted in Boronic acid, Bortezomib, Glutathione (GSH) Adducts, Imine amide, Millennium | Tagged , , | Leave a comment

How Are Fragments Optimized? A Retrospective Analysis of 145 Fragment Optimizations JMC 2013

György G. Ferenczy and György M. Keserű,  J. Med. Chem. Article ASAP

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“Detoxication” differs from “Detoxification”

According to Wikipedia

Two common patterns associated with Detoxication:

  1. A drug with potent pharmacological activity is converted to a major metabolite with markedly reduced or no pharmacological activity (e.g., Pentobarbital and Hydroxypentobarbital)
  2. A drug is converted to a metabolite with roughly equivalent or slightly lower pharmacological activity.

Detoxification is the process of removing toxins from the body, while detoxication is the process of preventing toxic entities from entering the body in the first place.

Examples of detoxification are: Administration of chelators for heavy metal poisoning, hyperbaric oxygen treatment for carbon monoxide poisoning and treatment of ethylene glycol poisoning with ethanol.

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The role of biotransformation enzymes in the development of renal injury and urothelial cancer caused by aristolochic acid: urgent questions and difficult answers. 2009

Stiborova M., Frei E., Arlt V.M., Schmeiser H.H.

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2009 Mar;153(1):5-11.

Enzymes may be involved in the bioactivation of AA include NAD(P)H:quinone oxidoreductase (NQO1), followed by cytochrome P450 (CYP) 1A1/2 in hepatic microsomes, and NADPH:CYP reductase (NPR) in renal microsomes. In addition, prostaglandin H synthase (cyclooxygenase, COX) highly expressed in urothelial tissue is also able to bioactivate AAI.

The oxidation of AAI to aristolochic acid Ia (AAIa) and conjugation reactions to form N– and O-glucuronide, the O-acetate and the O-sulfate esters have been suggested to be detoxification pathways.

Posted in 1A1, 1A2, Aristolochic Acid, Bioactivation, Biotransformation, Carcinogens, Cyclooxygenase (COX), NADPH P450 Reductase (NPR), NADPH Quninone Oxidoreductase | Tagged , , , | 3 Comments

Aristolochic Acid Nephropathy: Harbinger of a Global Iatrogenic Disease by Arthur P. Grollman 2013


Grollman, A. P., Environ Mol Mutagen. 2013 Jan; 54(1):1-7

Aristolochic acids are carcinogenic, mutagenic, and nephrotoxic compounds that cause Balkan endemic nephropathy and “Chinese herbs nephropathy”.

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Effect of Solvents on the Time-Dependent Inhibition of CYP3A4 and the Biotransformation of AZD3839 in Human Liver Microsomes and Hepatocytes, AstraZeneca DMD 2013

Aasa, J. et al. Drug Metab. Dispos. 2013 Jan;41(1):159-169.

Given the fact that M23 was observed in hepatocyte incubations, but not in microsomal incubations. AZD3839 might be a substrate for aldehyde oxidase and the oxidation very likely occurred on pyrimidine ring.



Posted in Drug Drug Interaction (DDI), Drug Metabolism, Solvent Effects, Time-dependent Inhibition (TDI) | Tagged , , | Leave a comment