Cytochrome P450 binding studies of novel tacrine derivatives: Predicting the risk of hepatotoxicity

McEneny‐King, Alanna; Osman, Wesseem; Edginton, Andrea N.; Rao, Praveen P.N.

doi:10.1016/j.bmcl.2017.04.006

Cited by 26 publications

(9 citation statements)

References 27 publications

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“…In developing tacrine hybrids, it is important to keep the potential hepatotoxic effect in mind. Linking or coupling with hepatoprotective compounds can reduce or even eliminate such a side effect. − …”

Section: Introductionmentioning

confidence: 99%

Dual-Acting Cholinesterase–Human Cannabinoid Receptor 2 Ligands Show Pronounced Neuroprotection in Vitro and Overadditive and Disease-Modifying Neuroprotective Effects in Vivo

et al. 2019

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We have designed and synthesized a series of 14 hybrid molecules out of the cholinesterase (ChE) inhibitor tacrine and a benzimidazole-based human cannabinoid receptor subtype 2 (hCB2R) agonist and investigated them in vitro and in vivo. The compounds are potent ChE inhibitors, and for the most promising hybrids, the mechanism of human acetylcholinesterase (hAChE) inhibition as well as their ability to interfere with AChE-induced aggregation of β-amyloid (Aβ), and Aβ self-aggregation was assessed. All hybrids were evaluated for affinity and selectivity for hCB1R and hCB2R. To ensure that the hybrids retained their agonist character, the expression of cAMP-regulated genes was quantified, and potency and efficacy were determined. Additionally, the effects of the hybrids on microglia activation and neuroprotection on HT-22 cells were investigated. The most promising in vitro hybrids showed pronounced neuroprotection in an Alzheimer’s mouse model at low dosage (0.1 mg/kg, i.p.), lacking hepatotoxicity even at high dose (3 mg/kg, i.p.).

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Section: Introductionmentioning

confidence: 99%

Dual-Acting Cholinesterase–Human Cannabinoid Receptor 2 Ligands Show Pronounced Neuroprotection in Vitro and Overadditive and Disease-Modifying Neuroprotective Effects in Vivo

et al. 2019

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“…Other minor metabolites were analyzed and identified as products of compound 12 degradation and hydroxylation (for further details see Figures S3–S8 in the Supporting Information). We did not identify any of the known metabolites responsible for the hepatotoxic effect of tacrine, although we have found traces of tacrine (M5) and the metabolites M3 and M4 that contain hydroxylated tacrine fragments (Figures S4–S6 in the Supporting Information).…”

Section: Resultsmentioning

confidence: 80%

Novel Multitarget-Directed Ligands Aiming at Symptoms and Causes of Alzheimer’s Disease

Więckowska

Wichur

Godyń

et al. 2018

ACS Chem. Neurosci.

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Alzheimer's disease (AD) is a major public health problem, which is due to its increasing prevalence and lack of effective therapy or diagnostics. The complexity of the AD pathomechanism requires complex treatment, e.g. multifunctional ligands targeting both the causes and symptoms of the disease. Here, we present new multitarget-directed ligands combining pharmacophore fragments that provide a blockade of serotonin 5-HT receptors, acetyl/butyrylcholinesterase inhibition, and amyloid β antiaggregation activity. Compound 12 has displayed balanced activity as an antagonist of 5-HT receptors ( K = 18 nM) and noncompetitive inhibitor of cholinesterases (IC = 14 nM, IC = 22 nM). In further in vitro studies, compound 12 has shown amyloid β antiaggregation activity (IC = 1.27 μM) and ability to permeate through the blood-brain barrier. The presented findings may provide an excellent starting point for further studies and facilitate efforts to develop new effective anti-AD therapy.

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“…Acetaminophen, amiodarone, desipramine, tacrine, and tolcapone are reportedly metabolized by CYP3A4 and carry a risk of hepatotoxicity. ( 18 , 19 , 20 , 21 , 22 ) Leflunomide is mainly metabolized by CYP2C9. ( 23 ) When these cells were treated with acetaminophen, desipramine, tacrine, or tolcapone, cell viabilities were significantly higher in CYP3A4‐KO HLCs than in WT HLCs.…”

Section: Resultsmentioning

confidence: 99%

In Vitro Model for a Drug Assessment of Cytochrome P450 Family 3 Subfamily A Member 4 Substrates Using Human Induced Pluripotent Stem Cells and Genome Editing Technology

et al. 2021

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In drug development, a system for predicting drug metabolism and drug‐induced toxicity is necessary to ensure drug safety. Cytochrome P450 family 3 subfamily A member 4 (CYP3A4) is an important drug‐metabolizing enzyme expressed in the liver and small intestine, and predicting CYP3A4‐mediated drug metabolism and drug‐induced toxicity is essential. We previously developed procedures to differentiate human induced pluripotent stem (iPS) cells into hepatocyte‐like cells (HLCs) or intestinal epithelial‐like cells (IECs) with a fetal phenotype as well as a highly efficient genome editing technology that could enhance the homologous recombination efficiency at any locus, including CYP3A4. By using human iPS cells and our genome editing technology, we generated CYP3A4‐knockout (KO) iPS cell‐derived HLCs and IECs for the evaluation of CYP3A4‐mediated drug metabolism and drug‐induced toxicity. CYP3A4 deficiency did not affect pluripotency and hepatic and intestinal differentiation capacities, and CYP3A4 activity was entirely eradicated by CYP3A4 KO. Off‐target effects (e.g., inhibition of bile acid excretion) were hardly observed in CYP3A4‐KO cells but were observed in CYP3A4 inhibitor‐treated (e.g., ketoconazole) cells. To evaluate whether drug‐induced hepatotoxicity and enterotoxicity could be predicted using our model, we exposed CYP3A4‐KO HLCs and IECs to acetaminophen, amiodarone, desipramine, leflunomide, tacrine, and tolcapone and confirmed that these cells could predict CYP3A4‐mediated toxicity. Finally, we examined whether the therapeutic effects of an anti‐hepatitis C virus (HCV) drug metabolized by CYP3A4 would be predicted using our model. CYP3A4‐KO HLCs were treated with asunaprevir (antiviral drug metabolized by CYP3A4) after HCV infection, and the anti‐viral effect was indeed strengthened by CYP3A4 KO. Conclusion: We succeeded in generating a novel evaluation system for prediction of CYP3A4‐mediated drug metabolism and drug‐induced toxicity.

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Cytochrome P450 binding studies of novel tacrine derivatives: Predicting the risk of hepatotoxicity

Cited by 26 publications

References 27 publications

Dual-Acting Cholinesterase–Human Cannabinoid Receptor 2 Ligands Show Pronounced Neuroprotection in Vitro and Overadditive and Disease-Modifying Neuroprotective Effects in Vivo

Dual-Acting Cholinesterase–Human Cannabinoid Receptor 2 Ligands Show Pronounced Neuroprotection in Vitro and Overadditive and Disease-Modifying Neuroprotective Effects in Vivo

Novel Multitarget-Directed Ligands Aiming at Symptoms and Causes of Alzheimer’s Disease

In Vitro Model for a Drug Assessment of Cytochrome P450 Family 3 Subfamily A Member 4 Substrates Using Human Induced Pluripotent Stem Cells and Genome Editing Technology

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