Hi all,
Thanks for the info @Yosukemino @David . Maybe asking some support here, considering the part of âWeak Beta EWGs may increase potencyâ. What about amides? Should it be considered a deactivating feature, activating one or none of them?
For example the following sub-structure:
This is where the specific definitions of these groups come into play⊠our definition of the âweak b-EWGsâ included all the carbonyl derivatives, including amides - this gives the conceptually very clear pattern of â*C=O is weakâ.
However, as Iâve stated, the potency-increasing effect of these is driven by the ketones. The EMA have taken a different âcutâ of the data, listing effectively all C=O compounds alongside the existing âstrongâ EWGs, but then excluding ketones specifically from the list. This has the same effect of separating the potent ketones from the compounds we expect to be reduced in potency, but allows the other carbonyl-derived EWGs - including amides - to be considered as potency-reducing features, increasing (significantly) the number of compounds considered to have EWGs.
Thanks David, very clear explanation of my question and the topic in general.
Thank you David
i donât have example for now but if i get one, i will definitely share.
@Yosukemino dear could you please advise on the limit of n-nitroso-vonoprazan based on the scoring system
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.
Dear, i think the following:
Of course, I may need to refresh my chemistry knowledge, so please accept my apology of Iâm wrong @Yosukemino 
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.
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.
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
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:
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.
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.
Thatâs really interesting explanation! Donât you think that a glossary or definition list should accompany such guidelines to ensure eliminating any misunderstanding or misinterpretation?
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.
