Bioactivation of 6,7-dimethyl-2,4-di-1-pyrrolidinyl-7H-pyrrolo[2,3-d]pyrimidine (U-89843) to reactive intermediates that bind covalently to macromolecules and produce genotoxicity.

  title={Bioactivation of 6,7-dimethyl-2,4-di-1-pyrrolidinyl-7H-pyrrolo[2,3-d]pyrimidine (U-89843) to reactive intermediates that bind covalently to macromolecules and produce genotoxicity.},
  author={Z Y Zhao and Kenneth Koeplinger and G. E. Padbury and M J Hauer and Gordon Bundy and Lee S. Banitt and Theresa M. Schwartz and David C. Zimmermann and Philip R. Harbach and J. K. Mayo and C. S. Aaron},
  journal={Chemical research in toxicology},
  volume={9 8},
U-89843 is a novel pyrrolo[2,3-d]pyrimidine antioxidant with prophylactic activity in animal models of lung inflammation. During preclinical safety evaluation, U-89843 was found to give a positive response in the in vitro unscheduled DNA synthesis (UDS) assay, an assay which measures DNA repair following chemically-induced DNA damage in metabolically competent rat hepatocytes. Incubation of [14C]U-89843 with liver microsomes resulted in covalent binding of radioactive material to macromolecules… Expand
9 Citations
Contribution of serum protein association to discrepancy between the in vivo and in vitro UDS results for 6,7-dimethyl-2,4-di-1-pyrrolidinyl-7H-pyrrolo[2,3-d]pyrimidine (U-89843).
The results suggest that the effect of serum protein should be considered when comparing serum-free in vitro UDS and in vivo UDS results for highly serum protein bound compounds. Expand
Stereoselective hydroxylation of nonpeptidic HIV protease inhibitors by CYP2D6.
The major oxidative biotransformation pathway of PNU-106893 which occurs in microsomal incubations appears to be hydroxylation of the phenylethyl side chain attached to the C-6 carbon of the dihydropyrone ring. Expand
Identification and characterization of in silico, in vivo, in vitro, and reactive metabolites of infigratinib using LC-ITMS: bioactivation pathway elucidation and in silico toxicity studies of its metabolites
Infigratinib (INF) is a novel, small molecule that is orally administered to inhibit human fibroblast growth factor receptors (FGFRs), which are a family of receptor tyrosine kinases that may beExpand
Reactive intermediates and bioactivation pathways characterization of avitinib by LC–MS/MS: In vitro metabolic investigation
The generation of reactive metabolites in avitinib metabolism was investigated using rat liver microsomes while adding capturing agents, viz potassium cyanide for reactive iminium intermediates, GSH for iminoquinones and methoxylamine for aldehyde forming stable adducts which are identifiable by LC–MS/MS. Expand
Bioactivation I: Bioactivation by Cytochrome P450s
Metabolism reactions generally result in detoxification of xenobiotics and are accompanied by the formation of chemically stable metabolites, which are devoid of pharmacological or toxicologicalExpand
Antimicrobial activity of small beta-peptidomimetics based on the pharmacophore model of short cationic antimicrobial peptides.
Small amphipathic beta-peptidomimetics may be a promising class of antimicrobial agents by means of having a similar range of potency and selectivity as larger cationic antimicrobial peptides in addition to improved enzymatic stability and lower costs of production. Expand
Improving the decision-making process in structural modification of drug candidates: reducing toxicity.
This review highlights the strategies for the decision-making process involving substructures that, when found in drugs, can form reactive metabolites and are involved in toxicities in humans; the tools used to reduce IDRs are also discussed. Expand
Minimizing the Potential for Drug Bioactivation of Drug Candidates to Success in Clinical Development
The recent efforts to overcome and assess the problem of reactive metabolites in drug discovery and development are discussed, which might help to evaluate the safety profile of new drug candidates for idiosyncratic drug reactions (IDRs) during the preclinical phase. Expand