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Chemical Research in Toxicology
pubs.acs.org/crt
■
Robert A. Jolly − Toxicology, LRL, Eli Lilly and Company,
Indianapolis, Indiana 46285, United States; orcid.org/
0000-0001-7106-830X; Email: jolly_robert_a@lilly.com
SUMMARY AND CONCLUSIONS
In the present study, we applied QM calculations on dialkyl
substituted N-nitrosamines, N-methyl alkyl nitrosamines, Nnitroso pyrrolidines, N-nitroso piperidine, N-nitroso piperazine, N-nitroso morpholine, N-nitroso thiomorpholine, Nnitroso aromatics to explain the variation in potencies within
classes of molecules and to differentiate carcinogenic and
noncarcinogenicity metabolic pathways. In most of the
nitrosamines studied in this work, the CPCA scores were
found to be more conservative than the actual AIs derived
from the experimental TD50 values. Specifically, all the Nmethyl aromatic nitrosamines fall under category 2 which
recommends 100 ng/day while the actual TD50 values are
higher and nondiscrete. This underscores the need for further
refinement of the CPCA where QM modeling can further
assist in rationalizing and correcting the AI estimation. While
our results broadly support the recent rational classification in
the CPCA methodology proposed by EMA and FDA (e.g., the
doubly substituted electron-withdrawing groups increase
deactivating features thereby decreasing the potency), our
QM analysis further showed that electron-withdrawing groups
increase the activation energies for all the reactions involved in
the carcinogenic metabolism (Figure 5). Furthermore, we have
showcased several examples herein where QM modeling
provided a meaningful rationale for their reactivity including
noncarcinogens, and where CPCA classification falls short.
For the quantitative modeling of TD50 and estimation of AI
limits, several studies suggest that local QSAR models using
QM parameters can allow for the estimation of AI values.20,43
In this regard, we have used the evaluation of IR frequency as a
surrogate for radical reactivity showing a high correlation to
TD50s and used that analysis to support lower potency for
several N-methyl aromatic NDSRIs (not included in this
study). This SAR analysis was supported experimentally by in
vivo mutagenicity work (Jolly et al. in progress). These results
from QM modeling of mechanistic pathways can be used for
weight evidence arguments to support AI estimation of
NDSRIs. Additionally, understanding the competitive metabolic pathways for sulfation, glucuronidation, demethylation
and denitrosation could potentially help in justifying AI for
NDSRIs. Future work will describe other nitrosamine
chemistry methods using QM parameters with a focus on
competing metabolic pathways.
■
Authors
Sriman De − Synthetic Molecule Design and Development, Eli
Lilly Services India Pvt Ltd, Bengaluru 560103, India
Bishnu Thapa − Discovery Chemistry Research and
Technology, LRL, Eli Lilly and Company, Indianapolis,
Indiana 46285, United States
Scott A. Frank − Synthetic Molecule Design and Development,
Eli Lilly and Company, Indianapolis, Indiana 46285, United
States; orcid.org/0000-0001-6680-9695
Paul D. Cornwell − Toxicology, LRL, Eli Lilly and Company,
Indianapolis, Indiana 46285, United States; orcid.org/
0009-0004-9786-774X
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.chemrestox.4c00087
Author Contributions
CRediT: Sriman De data curation, formal analysis, methodology, writing-original draft; Bishnu Thapa conceptualization,
formal analysis, investigation, methodology, writing-original
draft; Fareed Bhasha Sayyed conceptualization, data curation,
formal analysis, investigation, methodology, software, validation, writing-original draft; Scott A. Frank investigation,
resources, supervision, writing-review & editing; Paul D
Cornwell writing-review & editing; Robert A Jolly conceptualization, investigation, project administration, writing-original
draft, writing-review & editing.
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
The authors thank David Ackley, Douglas Roepke, and Alison
Campbell Brewer for reviewing this manuscript. Support from
Jon Day for the cover page design.
■
REFERENCES
(1) Beard, J. C.; Swager, T. M. An Organic Chemist’s Guide to NNitrosamines: Their Structure, Reactivity, and Role as Contaminants.
J. Org. Chem. 2021, 86 (3), 2037−2057.
(2) ICH-M7. Assessment and Control of DNA Reactive (Mutagenic)
Impurities in Pharmaceuticals To Limit Potential Carcinogenic Risk;
ICH, 2017. https://database.ich.org/sites/default/files/M7_R1_
Guideline.pdf (accessed on 29th August 2023).
(3) Magee, P. N.; Barnes, J. M. The Production of Malignant
Primary Hepatic Tumours in the Rat by Feeding Dimethylnitrosamine. Br. J. Cancer 1956, 10, 114−122.
(4) Bogovski, P.; Bogovski, S. Animal species in which N-nitroso
compounds induce cancer. Int. J. Cancer 1981, 27, 471−474.
(5) Bartsch, H.; Montesano, R. Relevance of nitrosamines to human
cancer. Carcinogenisis 1984, 5, 1381−1393.
(6) Preussmann, R. Public health significance of environmental Nnitroso compounds; IARC Scientific Publication, 1983; Vol. 45, pp. 3−
17.
(7) US FDA. Announces Voluntary Recall of Several Medicines
Containing Valsartan Following Detection of an Impurity. Available
online: https://www.fda.gov/drugs/drug-safety-and-availability/
recalls-angiotensin-ii-receptor-blockers-arbs-including-valsartanlosartan-and-irbesartan (accessed on 13th August 2023).
(8) Bharate, S. S. Critical Analysis of Drug Product Recalls due to
Nitrosamine Impurities. J. Med. Chem. 2021, 64 (6), 2923−2936.
(9) Nitrosamine impurities; European Medicines Agency, 2023.
https://www.ema.europa.eu/en/human-regulatory/post-
ASSOCIATED CONTENT
* Supporting Information
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.chemrestox.4c00087.
Cartesian coordinates of all the reactants, intermediates
and transition states involved for the molecules 1−35,
Gibbs free energy values, and high spin and low spin
activation energies for the aromatic molecules (PDF)
Nitrosamine potency information (ZIP)
■
Article
AUTHOR INFORMATION
Corresponding Authors
Fareed Bhasha Sayyed − Synthetic Molecule Design and
Development, Eli Lilly Services India Pvt Ltd, Bengaluru
560103, India; orcid.org/0000-0001-8364-4810;
Email: sayyed_fareed_bhasha@lilly.com
1021
21 / 34 ページ
https://doi.org/10.1021/acs.chemrestox.4c00087
Chem. Res. Toxicol. 2024, 37, 1011−1022
pubs.acs.org/crt
■
Robert A. Jolly − Toxicology, LRL, Eli Lilly and Company,
Indianapolis, Indiana 46285, United States; orcid.org/
0000-0001-7106-830X; Email: jolly_robert_a@lilly.com
SUMMARY AND CONCLUSIONS
In the present study, we applied QM calculations on dialkyl
substituted N-nitrosamines, N-methyl alkyl nitrosamines, Nnitroso pyrrolidines, N-nitroso piperidine, N-nitroso piperazine, N-nitroso morpholine, N-nitroso thiomorpholine, Nnitroso aromatics to explain the variation in potencies within
classes of molecules and to differentiate carcinogenic and
noncarcinogenicity metabolic pathways. In most of the
nitrosamines studied in this work, the CPCA scores were
found to be more conservative than the actual AIs derived
from the experimental TD50 values. Specifically, all the Nmethyl aromatic nitrosamines fall under category 2 which
recommends 100 ng/day while the actual TD50 values are
higher and nondiscrete. This underscores the need for further
refinement of the CPCA where QM modeling can further
assist in rationalizing and correcting the AI estimation. While
our results broadly support the recent rational classification in
the CPCA methodology proposed by EMA and FDA (e.g., the
doubly substituted electron-withdrawing groups increase
deactivating features thereby decreasing the potency), our
QM analysis further showed that electron-withdrawing groups
increase the activation energies for all the reactions involved in
the carcinogenic metabolism (Figure 5). Furthermore, we have
showcased several examples herein where QM modeling
provided a meaningful rationale for their reactivity including
noncarcinogens, and where CPCA classification falls short.
For the quantitative modeling of TD50 and estimation of AI
limits, several studies suggest that local QSAR models using
QM parameters can allow for the estimation of AI values.20,43
In this regard, we have used the evaluation of IR frequency as a
surrogate for radical reactivity showing a high correlation to
TD50s and used that analysis to support lower potency for
several N-methyl aromatic NDSRIs (not included in this
study). This SAR analysis was supported experimentally by in
vivo mutagenicity work (Jolly et al. in progress). These results
from QM modeling of mechanistic pathways can be used for
weight evidence arguments to support AI estimation of
NDSRIs. Additionally, understanding the competitive metabolic pathways for sulfation, glucuronidation, demethylation
and denitrosation could potentially help in justifying AI for
NDSRIs. Future work will describe other nitrosamine
chemistry methods using QM parameters with a focus on
competing metabolic pathways.
■
Authors
Sriman De − Synthetic Molecule Design and Development, Eli
Lilly Services India Pvt Ltd, Bengaluru 560103, India
Bishnu Thapa − Discovery Chemistry Research and
Technology, LRL, Eli Lilly and Company, Indianapolis,
Indiana 46285, United States
Scott A. Frank − Synthetic Molecule Design and Development,
Eli Lilly and Company, Indianapolis, Indiana 46285, United
States; orcid.org/0000-0001-6680-9695
Paul D. Cornwell − Toxicology, LRL, Eli Lilly and Company,
Indianapolis, Indiana 46285, United States; orcid.org/
0009-0004-9786-774X
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.chemrestox.4c00087
Author Contributions
CRediT: Sriman De data curation, formal analysis, methodology, writing-original draft; Bishnu Thapa conceptualization,
formal analysis, investigation, methodology, writing-original
draft; Fareed Bhasha Sayyed conceptualization, data curation,
formal analysis, investigation, methodology, software, validation, writing-original draft; Scott A. Frank investigation,
resources, supervision, writing-review & editing; Paul D
Cornwell writing-review & editing; Robert A Jolly conceptualization, investigation, project administration, writing-original
draft, writing-review & editing.
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
The authors thank David Ackley, Douglas Roepke, and Alison
Campbell Brewer for reviewing this manuscript. Support from
Jon Day for the cover page design.
■
REFERENCES
(1) Beard, J. C.; Swager, T. M. An Organic Chemist’s Guide to NNitrosamines: Their Structure, Reactivity, and Role as Contaminants.
J. Org. Chem. 2021, 86 (3), 2037−2057.
(2) ICH-M7. Assessment and Control of DNA Reactive (Mutagenic)
Impurities in Pharmaceuticals To Limit Potential Carcinogenic Risk;
ICH, 2017. https://database.ich.org/sites/default/files/M7_R1_
Guideline.pdf (accessed on 29th August 2023).
(3) Magee, P. N.; Barnes, J. M. The Production of Malignant
Primary Hepatic Tumours in the Rat by Feeding Dimethylnitrosamine. Br. J. Cancer 1956, 10, 114−122.
(4) Bogovski, P.; Bogovski, S. Animal species in which N-nitroso
compounds induce cancer. Int. J. Cancer 1981, 27, 471−474.
(5) Bartsch, H.; Montesano, R. Relevance of nitrosamines to human
cancer. Carcinogenisis 1984, 5, 1381−1393.
(6) Preussmann, R. Public health significance of environmental Nnitroso compounds; IARC Scientific Publication, 1983; Vol. 45, pp. 3−
17.
(7) US FDA. Announces Voluntary Recall of Several Medicines
Containing Valsartan Following Detection of an Impurity. Available
online: https://www.fda.gov/drugs/drug-safety-and-availability/
recalls-angiotensin-ii-receptor-blockers-arbs-including-valsartanlosartan-and-irbesartan (accessed on 13th August 2023).
(8) Bharate, S. S. Critical Analysis of Drug Product Recalls due to
Nitrosamine Impurities. J. Med. Chem. 2021, 64 (6), 2923−2936.
(9) Nitrosamine impurities; European Medicines Agency, 2023.
https://www.ema.europa.eu/en/human-regulatory/post-
ASSOCIATED CONTENT
* Supporting Information
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.chemrestox.4c00087.
Cartesian coordinates of all the reactants, intermediates
and transition states involved for the molecules 1−35,
Gibbs free energy values, and high spin and low spin
activation energies for the aromatic molecules (PDF)
Nitrosamine potency information (ZIP)
■
Article
AUTHOR INFORMATION
Corresponding Authors
Fareed Bhasha Sayyed − Synthetic Molecule Design and
Development, Eli Lilly Services India Pvt Ltd, Bengaluru
560103, India; orcid.org/0000-0001-8364-4810;
Email: sayyed_fareed_bhasha@lilly.com
1021
21 / 34 ページ
https://doi.org/10.1021/acs.chemrestox.4c00087
Chem. Res. Toxicol. 2024, 37, 1011−1022