Thank you for asking me, @Alaaelkazak. I posted the result of the calculation in the following thread. Category 1 is appropriate for N-nitroso-vonoprazan.
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Dear, i think the following:
- The pyrrole group is electron withdrawing attached to the alpha carbon on one side (+1)
- The pyrrole group is not an aryl (itâs neither benzylic nor pseudo-benzylic)
Accordingly, 1+1= 2. This corresponds to 100 ng/day which is very near to the FDA set limit of 96 ng/day.
What do you think?
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Of course, I may need to refresh my chemistry knowledge, so please accept my apology of Iâm wrong @Yosukemino 
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Thank you for correcting me, @Alaaelkazak.
According to the EMA Q&A, available EWGs as deactivating features are those described in @kpcross and @David 's paper.
**Excludes carboxylic acid and aryl (counted separately), and ketone (conflicting data). Additional electron withdrawing group examples are limited to those described in Cross KP and Ponting DJ, 2021, Developing Structure-Activity Relationships for N-Nitrosamine Activity, Comput Toxicol, 20:100186, where they are referred to as âÎČ-carbon electron withdrawing groups."
The pyrrole group can not be used as electron withdrawing group. And N-nitroso-vonoprazan will be in category 1(Potency Score: 1), I think.
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To confirm, you have excluded the activating feature and accordingly only the count of hydrogen will be considered. Am I right?
Please do not miss the post from @ccdw regarding activating feature âMethyl group bonded to beta-carbonâ
Iâm sorry I could not find why Pyrrole is not aryl. As the benzofuranyl group is aryl, Pyrrole can be aryl, I think. If so, the aryl group is excluded from EWG. And the aryl group is considered an Activating Feature. The potency score is zero in that case.
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Please refer to these links for aryl definition:
Aryl should have a benzen ring and thatâs not the case I think here. Either ways, both scores of 1 and 0 will imply 18 ng/day limit. Really thanks for your help and extended support
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Engaging discourse on the subject of organic chemistry!
@Alaaelkazak, within the pyrrole molecule, the lone pair of electrons residing on the nitrogen atom effectively contributes to the count of six Ï electrons required for the establishment of aromaticity within the system, as you can see here:
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Why FDA set limit of 96 ng/day for N-nitroso-vonoprazan, any other scientific evaluation is there.
Moreover we can said there is again different approaches regulatory to regulatory.
Iâm afraid that link is incorrect, not only in comparison to what I was taught (my undergrad was organic chemistry) but also specifically in the context of how the term aryl is used in the nitrosamine SAR work - we have used both in discourse and the underlying patterns, (which simply require an aromatic atom there, see below) the term to mean all aromatic systems. As an aside, the strength of aromatic systems can vary, in that some are more effectively-delocalised than others, but weâve considered essentially anything that obeys Huckelâs rule - as @lucas10mauriz has explained this does - or more precisely anything accepted by the computational representation, whether SMARTS or any internal representation tool, as aromatic. In practical terms for the underlying patterns, this means that the SMARTS definition of this feature will be something along the lines of aCNN=O or cCNN=O.
To further confusion, we have referred to this occasionally as a benzylic-like a-carbon, which does formally imply c1ccccc1CNN=O, but that is simply because the word arylic doesnât exist, and weâve always made the effort to clarify that we do mean all aromatic systems in this case.
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A limit of 96 is almost certainly derived by read-across from NDMA, which can be at least somewhat justified for any N-methyl-N-nitroso group (though thereâs normally a more precise analogue than this). Remember that the FDA have not (yet? my understanding is that there has been regulatory collaboration on this so we might see changes in future) published the CPCA, so the approach is currently formally only valid for EMA submissions and any health authority that has specifically written their guidance as âcopy EMA exactlyâ.
The way the EMA guidance is written, the CPCA should be performed first, but can be over-ruled with robust data, either a robust read-across or experimental toxicity data.
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Thatâs really interesting explanation! Donât you think that a glossary or definition list should accompany such guidelines to ensure eliminating any misunderstanding or misinterpretation?
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I think âarylâ and âaromaticâ are generally understood as described - especially when looking at the examples in the guidance and the limits for those compounds that have CPCA limits⊠in terms of a specific glossary, I suspect weâre out of luck due to the decision to refer the electron-withdrawing group (EWG) definitions back to Cross & Ponting rather than enumerating them.
My general thought would be to ask here (see for example the discussions of beta-methyl groups in another thread) if there are any features that the precise definitions of which are unclear - for example, I can state with some confidence that the EWG list, though there are many other groups that do withdraw electrons, is pattern-able as â*A=,#Q, *CF3, not *C([C,H])=O and not *COOHâ.
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@Yosukemino i think this structure is the correct one
https://www.tga.gov.au/news/safety-alerts/sitagliptin#:~:text=7-nitroso-3-(trifluoromethyl)-5%2C6%2C7%2C8-tetrahydro[1%2C2%2C4]triazolo-[4%2C3-%20a]pyrazine.
that is I believe the structure - itâs not nitroso-sitagliptin itself, rather the nitrosamine of an impurity of sitagliptin.
It has been assigned a compound-specific limit of 37 ng/day by read-across from nitroso-1,2,3,6-tetrahydropyridine (with the aromatic group assumed to be comparable to the double bond there and the âarylicâ position like the allylic in NTHP), though by CPCA would have a limit of 100:
(2,2) for H-count = 1
In a generic 6-membered ring = 2
Aromatic group at b-position activating it = -1
Total 2, limit 100 ng/day
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So in those case, what overrule⊠the smallest AI or the CPCA AI limit?
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@David Thanks for clarity on subject.
However still question is that, which approach for determination AI is suitable and valid, either SAR or CPCA and how it will be decided.
My understanding is that in this case, because there is a defined limit, that takes precedence, however in the general case CPCA should be tried first but can be overridden if needed (and it will be - there are a lot of nitrosamines still in categories 1-3!) by read-across.
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