Overcoming Time-Dependent Inhibition (TDI) of Cytochrome P450 3A4 (CYP3A4) Resulting from Bioactivation of a Fluoropyrimidine Moiety

Mandal, Mihir; Mitra, Kaushik; Grotz, Diane E.; Lin, Xinjie; Palamanda, Jairam; Kumari, Pramila; Buevich, Alexei V.; Caldwell, John P.; Chen, Xia; Cox, Kathleen; Favreau, Leonard; Hyde, Lynn A.; Kennedy, Matthew; Kuvelkar, Reshma; Liu, Xiaoxang; Mazzola, Robert; Parker, Eric M.; Rindgen, Diane; Sherer, Edward C.; Wang, Hongwu; Zhu, Zhiwei; Stamford, Andrew W.; Cumming, Jared N.

doi:10.1021/acs.jmedchem.8b01326

Cited by 12 publications

(15 citation statements)

References 21 publications

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“…Additional structure–liability studies confirmed that dual substitution at the 4- and 6-positions of the 5-fluoropyrimidine ring was sufficient to ameliorate the TDI. This protective effect was exemplified by the 4,6-dimethyl-5-fluoropyrimidine analogue 465 , which demonstrated 10-fold weaker inhibition of CYP3A4 relative to 464 …”

Section: Fluorinated Aromaticsmentioning

confidence: 99%

“…This adduct would lose HF to afford 466 , which would then tautomerize to the observed product 467 . Alternatively, epoxide ring opening with loss of fluoride, as the result of anchimeric assistance by the pyrrolidine N atom, would produce a highly electrophilic quinone iminium derivative that could either add GSH to produce 467 or be reduced to give 468 . Further support for this postulate was provided by studies of the fluorophenyl and unsubstituted pyrimidine analogues, neither of which resulted in CYP3A4 TDI (IC 50 > 30 μM).…”

Section: Fluorinated Aromaticsmentioning

confidence: 99%

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Metabolic and Pharmaceutical Aspects of Fluorinated Compounds

et al. 2020

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The applications of fluorine in drug design continue to expand, facilitated by an improved understanding of its effects on physicochemical properties and the development of synthetic methodologies that are providing access to new fluorinated motifs. In turn, studies of fluorinated molecules are providing deeper insights into the effects of fluorine on metabolic pathways, distribution, and disposition. Despite the high strength of the C–F bond, the departure of fluoride from metabolic intermediates can be facile. This reactivity has been leveraged in the design of mechanism-based enzyme inhibitors and has influenced the metabolic fate of fluorinated compounds. In this Perspective, we summarize the literature associated with the metabolism of fluorinated molecules, focusing on examples where the presence of fluorine influences the metabolic profile. These studies have revealed potentially problematic outcomes with some fluorinated motifs and are enhancing our understanding of how fluorine should be deployed.

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Section: Fluorinated Aromaticsmentioning

confidence: 99%

Section: Fluorinated Aromaticsmentioning

confidence: 99%

Metabolic and Pharmaceutical Aspects of Fluorinated Compounds

et al. 2020

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“…The bioactivation of fluoropyrimidine is a rare occurrence and is contrary to documented cases that show that adding fluorine and nitrogen to aromatic rings can slow P450 metabolism. ,, Some fluoropyrimidine-containing compounds were being developed as BACE1 inhibitors 14 for the treatment of Alzheimer’s disease . The molecules investigated were found to have time-dependent inhibition (TDI) of CYP 3A4, a predominant P450 enzyme, indicating an increased potential for drug–drug interactions in the clinic .…”

Section: Aromatic Bioactivationmentioning

confidence: 99%

Metabolism and Bioactivation: It’s Time to Expect the Unexpected

Driscoll¹,

Sadlowski²,

Shah³

et al. 2020

J. Med. Chem.

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Improvements in in vitro ADME tools and pharmacokinetic prediction models have helped to shift attrition rates in early clinical trials from poor exposure to drug safety concerns, such as drug-induced liver injury (DILI). Assessing a new chemical entity’s potential for liver toxicity is an important consideration for the likely success of new drug candidates. Reactive intermediates produced during drug metabolism have been implicated as a cause of DILI, and their formation has been correlated to the addition of a black box warning on a drug label. In this work, we will present contemporary examples of the bioactivation of atypical structures usually regarded as benign and often used by medicinal chemists when attempting to avoid bioactivation. Medicinal chemistry strategies used to derisk bioactivation will be discussed, and an emphasis will be placed on the necessity of a multidisciplinary approach.

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“…62 Of note, the relative importance of the corresponding structural features was correctly recognized (Figure 6b). Additional examples [63][64][65] are provided in the Supporting Data and the accompanying code repos-…”

Section: Pharmacophore Motif Recognitionmentioning

confidence: 99%

Coloring Molecules with Explainable Artificial Intelligence for Preclinical Relevance Assessment

Jiménez-Luna

Škalič

Weskamp

et al. 2021

J. Chem. Inf. Model.

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Graph neural networks are able to solve certain drug discovery tasks such as molecular property prediction and \textit{de novo} molecule generation. However, these models are considered 'black-box' and 'hard-to-debug'. This study aimed to improve modeling transparency for rational molecular design by applying the integrated gradients explainable artificial intelligence (XAI) approach for graph neural network models. Models were trained for predicting plasma protein binding, cardiac potassium channel inhibition, passive permeability, and cytochrome P450 inhibition. The proposed methodology highlighted molecular features and structural elements that are in agreement with known pharmacophore motifs, correctly identified property cliffs, and provided insights into unspecific ligand-target interactions. The developed XAI approach is fully open-sourced and can be used by practitioners to train new models on other clinically-relevant endpoints. File list (2) download file view on ChemRxiv jimenez2020color.pdf (5.85 MiB) download file view on ChemRxiv molgrad_series.csv (13.15 KiB)

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Overcoming Time-Dependent Inhibition (TDI) of Cytochrome P450 3A4 (CYP3A4) Resulting from Bioactivation of a Fluoropyrimidine Moiety

Cited by 12 publications

References 21 publications

Metabolic and Pharmaceutical Aspects of Fluorinated Compounds

Metabolic and Pharmaceutical Aspects of Fluorinated Compounds

Metabolism and Bioactivation: It’s Time to Expect the Unexpected

Coloring Molecules with Explainable Artificial Intelligence for Preclinical Relevance Assessment

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