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1.
J Pharm Sci ; 112(12): 3005-3011, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37805074

RESUMO

N-Nitrosamines are a class of indirect acting mutagens, as their metabolic degradation leads to the formation of the DNA-alkylating diazonium ion. Following up on the in-silico identification of thousands of nitrosamines that can potentially be derived from small molecule drugs and their known impurities described in a previous publication, we have now re-analyzed this dataset to apply EMA's Carcinogenic Potency Categorization Approach (CPCA) introduced with the 16th revision of their Q&A document for Marketing Authorization Holders. We find that the majority of potential nitrosamines from secondary amine precursors belongs to potency categories 4 and 5, corresponding to an acceptable daily intake of 1500 ng, whereas nitrosamines from tertiary amine precursors distribute more evenly among all categories, resulting in a substantial number of structures that are assigned the more challenging acceptable intakes of 18 ng/day and 100 ng/day for potency categories 1 and 2, respectively. However, the nitrosative dealkylation pathway for tertiary amine is generally far slower than the direct nitrosation on secondary amines, with a direct nitrosation mechanism suspected only for structures featuring electron-rich (hetero)aromatic substituents. This allows for greater focus towards those structures that require further review, and we demonstrate that their number is not substantial. In addition, we reflect on the nitrosamine risk posed by secondary amine API impurities and demonstrate that based on the ICH Q3A/B identification threshold unknown impurities may exist that could be transformed to relevant amounts of NA. We also demonstrate that the analytical sensitivity required for the quantification of high potency nitrosamines can be problematic especially for high dose APIs. In summary, the regulatory framework rolled out with the latest Q&A document represents a substantial improvement compared with the previous situation, but further refinement through interaction between manufacturers, regulators, not-for-profit and academic institutions will be required to ensure patient access to vital medicines without compromising safety.


Assuntos
Nitrosaminas , Humanos , Nitrosaminas/química , Aminas/química , Preparações Farmacêuticas
2.
Regul Toxicol Pharmacol ; 144: 105490, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37659712

RESUMO

Expert review of two predictions, made by complementary (quantitative) structure-activity relationship models, to an overall conclusion is a key component of using in silico tools to assess the mutagenic potential of impurities as part of the ICH M7 guideline. In lieu of a specified protocol, numerous publications have presented best practise guides, often indicating the occurrence of common prediction scenarios and the evidence required to resolve them. A semi-automated expert review tool has been implemented in Lhasa Limited's Nexus platform following collation of these common arguments and assignment to the associated prediction scenarios made by Derek Nexus and Sarah Nexus. Using datasets primarily donated by pharmaceutical companies, an automated analysis of the frequency these prediction scenarios occur, and the likelihood of the associated arguments assigning the correct resolution, could then be conducted. This article highlights that a relatively small number of common arguments may be used to accurately resolve many prediction scenarios to a single conclusion. The use of a standardised method of argumentation and assessment of evidence for a given impurity is proposed to improve the efficiency and consistency of expert review as part of an ICH M7 submission.

3.
ALTEX ; 40(1): 34­52, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-35575642

RESUMO

The traditional paradigm for safety assessment of chemicals for their carcinogenic potential to humans relies heavily on a battery of well-established genotoxicity tests, usually followed up by long-term, high-dose rodent studies. There are a variety of problems with this approach, not least that the rodent may not always be the best model to predict toxicity in humans. Consequently, new approach methodologies (NAMs) are being developed to replace or enhance predictions coming from the existing assays. However, a combination of the data arising from NAMs is likely to be required to improve upon the current paradigm, and consequently a framework is needed to combine evidence in a meaningful way. Adverse outcome pathways (AOPs) represent an ideal construct on which to organize this evidence. In this work, a data structure outlined previously was used to capture AOPs and evidence relating to carcinogenicity. Knowledge held within the predictive system Derek Nexus was extracted, built upon, and arranged into a coherent network containing 37 AOPs. 60 assays and 351 in silico alerts were then associated with KEs in this network, and it was brought to life by associating data and contextualizing evidence and predictions for over 13,400 compounds. Initial investigations into using the network to view knowledge and reason between evidence in different ways were made. Organizing knowledge and evidence in this way provides a flexible framework on which to carry out more consistent and meaningful carcinogenicity safety assessments in many different contexts.


Assuntos
Rotas de Resultados Adversos , Humanos , Testes de Mutagenicidade/métodos , Carcinógenos/toxicidade , Emprego , Medição de Risco
4.
Regul Toxicol Pharmacol ; 133: 105200, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35662638

RESUMO

The Dermal Sensitisation Thresholds (DST) are Thresholds of Toxicological Concern, which can be used to justify exposure-based waiving when conducting a skin sensitisation risk assessment. This study aimed to update the published DST values by expanding the size of the Local Lymph Node Assay dataset upon which they are based, whilst assigning chemical reactivity using an in silico expert system (Derek Nexus). The potency values within the expanded dataset fitted a similar gamma distribution to that observed for the original dataset. Derek Nexus was used to classify the sensitisation activity of the 1152 chemicals in the expanded dataset and to predict which chemicals belonged to a High Potency Category (HPC). This two-step classification led to three updated thresholds: a non-reactive DST of 710 µg/cm2 (based on 79 sensitisers), a reactive (non-HPC) DST of 73 µg/cm2 (based on 331 sensitisers) and an HPC DST of 1.0 µg/cm2 (based on 146 sensitisers). Despite the dataset containing twice as many sensitisers, these values are similar to the previously published thresholds, highlighting their robustness and increasing confidence in their use. By classifying reactivity in silico the updated DSTs can be applied within a skin sensitisation risk assessment in a reproducible, scalable and accessible manner.


Assuntos
Dermatite Alérgica de Contato , Testes Cutâneos/normas , Simulação por Computador , Dermatite Alérgica de Contato/etiologia , Sistemas Inteligentes , Humanos , Ensaio Local de Linfonodo , Medição de Risco , Pele
5.
Methods Mol Biol ; 2425: 435-478, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35188642

RESUMO

Lhasa Limited have had a role in the in silico prediction of drug and other chemical toxicity for over 30 years. This role has always been multifaceted, both as a provider of predictive software such as Derek Nexus, and as an honest broker for the sharing of proprietary chemical and toxicity data. A changing regulatory environment and the drive for the Replacement, Reduction and Refinement (the 3Rs) of animal testing have led both to increased acceptance of in silico predictions and a desire for the sharing of data to reduce duplicate testing. The combination of these factors has led to Lhasa Limited providing a suite of products and coordinating numerous data-sharing consortia that do indeed facilitate a significant reduction in the testing burden that companies would otherwise be laboring under. Many of these products and consortia can be organized into workflows for specific regulatory use cases, and it is these that will be used to frame the narrative in this chapter.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Software , Animais , Simulação por Computador
6.
Genes Environ ; 42: 27, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32983286

RESUMO

The use of in silico predictions for the assessment of bacterial mutagenicity under the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) M7 guideline is recommended when two complementary (quantitative) structure-activity relationship (Q)SAR models are used. Using two systems may increase the sensitivity and accuracy of predictions but also increases the need to review predictions, particularly in situations where results disagree. During the 4th ICH M7/QSAR Workshop held during the Joint Meeting of the 6th Asian Congress on Environmental Mutagens (ACEM) and the 48th Annual Meeting of the Japanese Environmental Mutagen Society (JEMS) 2019, speakers demonstrated their approaches to expert review using 20 compounds provided ahead of the workshop that were expected to yield ambiguous (Q)SAR results. Dr. Chris Barber presented a selection of the reviews carried out using Derek Nexus and Sarah Nexus provided by Lhasa Limited. On review of these compounds, common situations were recognised and are discussed in this paper along with standardised arguments that may be used for such scenarios in future.

7.
Chemistry ; 21(8): 3257-63, 2015 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-25557473

RESUMO

Cu salts have been found to promote the cycloaddition reaction of sydnones and terminal alkynes, providing significant reduction in reaction times. Specifically, the use of Cu(OTf)2 is found to provide 1,3-disubstituted pyrazoles, whereas simply switching the promoter system to Cu(OAc)2 allows the corresponding 1,4-isomers to be produced. The mechanism of the Cu-effect in each case has been investigated by experimental and theoretical studies, and they suggest that Cu(OTf)2 functions by Lewis acid activation of the sydnone, whereas Cu(OAc)2 promotes formation of reactive Cu(I) acetylides.

8.
J Org Chem ; 78(8): 4049-64, 2013 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-23548035

RESUMO

We report the synthesis and some structural studies of 4-trifluoromethyl, 4-difluoromethyl-, and 4-monofluoromethylsydnones. All but the latter compounds are stable and represent effective precursors to a range of pyrazoles after cycloaddition reactions with alkynes. The cycloadditions are generally highly regioselective and provide 5-fluoromethylpyrazole products, although we have observed that Bn-substituted sydnones can provide an unexpected alkyne insertion mode that generates the 3-fluoromethyl isomer.


Assuntos
Alcinos/química , Sidnonas/síntese química , Catálise , Reação de Cicloadição , Estrutura Molecular , Sidnonas/química
9.
Org Lett ; 14(18): 4858-61, 2012 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-22934538

RESUMO

Two synthetic approaches to 4-trifluoromethylsydnones, a novel class of these mesoionic reagents, are reported. These compounds undergo regioselective alkyne cycloaddition reactions, thereby providing a general approach to 5-trifluoromethylpyrazoles. This method has been employed in a short formal synthesis of the herbicide fluazolate.


Assuntos
Alcinos/química , Herbicidas/síntese química , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Halogenados/síntese química , Pirazóis/síntese química , Reação de Cicloadição , Herbicidas/química , Herbicidas/farmacologia , Hidrocarbonetos Fluorados/química , Hidrocarbonetos Halogenados/química , Hidrocarbonetos Halogenados/farmacologia , Estrutura Molecular , Pirazóis/química , Pirazóis/farmacologia , Estereoisomerismo
10.
Org Biomol Chem ; 7(19): 4052-6, 2009 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-19763310

RESUMO

A concise synthesis of three members of the withasomnine family of natural products is reported. The synthesis features a regioselective sydnone-alkynylboronate cycloaddition followed by Suzuki cross coupling and silyl group removal, and marks the first divergent approach to this family of pyrazole based natural products.


Assuntos
Alcaloides/química , Alcaloides/síntese química , Pirazóis/química , Pirazóis/síntese química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Estereoisomerismo , Especificidade por Substrato , Sidnonas/química
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