Hi, @Pradpharma
N-nitroso-propanolol is considered a typo of N-nitroso-propranolol. Please add it, too.
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Thanks for sharing this example.
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Hi, @Pradpharma
Thank you for asking. Yes, you are right. I posted the example of N-nitroso-propranolol in the case study thread. Please check it.
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Hi,
I am not able to figure out how the alpha-hydrogen scoring is done based on the example provided in the EMA guideline.
Why is 0,3 = 2; 1,3 = 3; 2,2=1 and 2,3 =1
I am not a chemist, I hope someone can explain this part
Thank You
Regards
Sushant
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Dear @sushantkamath,
Thank you for asking good questions. You asked why is 0,3 = 2; 1,3 = 3; 2,2=1 and 2,3 =1. And Iโm not sure of the answer, but I know compounds with less score are vulnerable to metabolic activation by CYP. The alfa-hydroxylation step is the key to nitrosaminesโ carcinogenicity. I add the slide and link to Pontingโs presentation.
I guess the score was determined from the results of TD50 of lots of nitrosamines. In other words, the scoring system was built through validation with nitrosaminesโ toxicological data. Compounds with low scores have a tendency to be potent in carcinogenicity. And visualization thread may be helpful to understand the scoring system.
If you need further help, do not hesitate to ask us.
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Hi @Yosukemino,
Thank You.
I have gone through the presentation by Ponting as well as the Cross and Ponting publication. EMA has not included all the deactivating features from their publication in the Table, although they have cited the publication.
The problem with the scoring system is when we start to apply it for other possible NDSRIs for which no AI limits have been established. For eg: few NDSRIs have a score of (0,2) with two hydrogen atoms on only one alpha-carbon. These compounds may not have the methylene alpha-carbon or the ethyl group to provide a score of 3 or even 2. How do we then score (0,2)?
Regards
Sushant
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Iโm sorry, I couldnโt understand the structure you meant. If you kindly illustrate these structures, I may understand.
And I think compounds of (0,2) score with two hydrogen atoms on only one alpha-carbon are as follows;
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Hi @sushantkamath,
Please note that the EMA has itself mentioned the list is not exhaustive.
Coming to question on (0,2)- it would have been better, if the structure is known- that can be discussed well. Nevertheless, Thanks @Yosukemino - He brought in few structures, that may fit to your question, Where i am in opinion we need to assign scores based on availability of alpha-carbon hydrogens and also the reactivity of alpha-carbon hydrogens which depends on the surrounding environment and type of molecule.
Overall, it is fortunate we got some guidance through this EMA update, at the same time-โYesโ it may not address all complex NDSRIS right now-Hope it will do in future soon.
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For the specific question - my interpretation is tht the (0,2) combination is worth a CPCA score of 2, before the activating/deactivating features, if the side chain is specifically ethyl, which puts ethyl groups in the same bucket as the (0,3) methyl group. This is based on the comparable potency and metabolic lability of ethyl and methyl groups. All other CH2 groups are less labile and are worth a CPCA score of 3.
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Indeed, the increased steric bulk infers a dramatic reduction in potency. We essentially have three cases here in appendix A table 2, with some modulation between methyl and larger groups.
If the most-hindered side is CH2, then whether the right-hand side is CH2 or CH3 makes little difference, both sides can react and highly-reactive diazonium ions can form, hence the score of 1 - reflected in a number of potent carcinogens that match this unhindered pattern.
Isopropyl groups, as I have been saying for a number of years, lead to a dramatic reduction in potency, hence the score of 3 for either (1,3) or (1,2).
Aryl groups are interesting, because there are a few potent examples such as nitrosomethyl aniline (NMA or NMPA) which explains the lower score for (0,3), and ethyl groups are just as reactive as methyl hence the exception in (0,2). All other groups (other than activating groups) are less labile, making the rest of (0,2) have a score of 3. These also have some potential alternative mechanisms not available to the isopropyl ones, hence the lower scores for NMA and nitrosoethylaniline and ring-substituted derivatives.
As a caveat, tert-butyl groups [(0,0) (0,1), (0,2), (0,3) where the 0 is sp3], as well as the fully-hindered (0,1) and (1,1) have an effective CPCA score of >5, enough to make them category 4 if they did need the CPCA but of course donโt need it, and the only (3,3) is NDMA - which of course has a compound-specific limit. This is why not all permutations are in the CPCA.
(I really should have put my surname in my username hereโฆ I am the Ponting you mention)
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A morning spent feverishly calculating Potency Category values for various molecules - cross checking some against newly published limits (making sure I was doing it correctly and agreeing with the EMA) and creating new limits!!
In many cases better than I had dared to hope for!
Finally, as has been said all along, targets to work to. Now, as an industry, we can look at:-
- are our methods good enough to detect at the new limits (and down to 10% of them)?
- are levels in products acceptable to these new limits?
- how to reduce levels in products that are still problematic.
Fantastic to see such collaboration between the industry as whole to drive us to this position, being led by the science, with some outstanding contributions from individuals and organisations.
Now if we can only harmonize these limits globally (over to you FDA, ANVISA etc.) and also harmonize Less Than Lifetime limits. Or am I just greedy?
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Indeed a privilege to hear from you Dr. Ponting. Thank you for the detailed explanation. I want to congratulate you for the immense contribution you have made in this field. We were all waiting for agencies to accept a chemistry approach to set AI limits instead of relying on only in vivo studies. This new guideline comes as a breather to the pharmaceutical industry.
Thank You
Regards
Sushant
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Mark can you share your preliminary assessment on structures? I would be a tremendous didactic contribution!
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Community Members !!! @trust_user_a @trust_user_c @trust_user_b
By now, you are probably aware of the significant update published last Friday (July 7th) on EMAโs ๐๐ฎ๐๐ฌ๐ญ๐ข๐จ๐ง๐ฌ ๐๐ง๐ ๐๐ง๐ฌ๐ฐ๐๐ซ๐ฌ ๐๐จ๐ซ ๐ฆ๐๐ซ๐ค๐๐ญ๐ข๐ง๐ ๐๐ฎ๐ญ๐ก๐จ๐ซ๐ข๐ฌ๐๐ญ๐ข๐จ๐ง ๐ก๐จ๐ฅ๐๐๐ซ๐ฌ/๐๐ฉ๐ฉ๐ฅ๐ข๐๐๐ง๐ญ๐ฌ ๐จ๐ง ๐ญ๐ก๐ ๐๐๐๐ ๐๐ฉ๐ข๐ง๐ข๐จ๐ง ๐๐จ๐ซ ๐ญ๐ก๐ ๐๐ซ๐ญ๐ข๐๐ฅ๐ ๐(๐) ๐จ๐ ๐๐๐ ๐ฎ๐ฅ๐๐ญ๐ข๐จ๐ง (๐๐) ๐๐จ ๐๐๐/๐๐๐๐ ๐ซ๐๐๐๐ซ๐ซ๐๐ฅ ๐จ๐ง ๐ง๐ข๐ญ๐ซ๐จ๐ฌ๐๐ฆ๐ข๐ง๐ ๐ข๐ฆ๐ฉ๐ฎ๐ซ๐ข๐ญ๐ข๐๐ฌ ๐ข๐ง ๐ก๐ฎ๐ฆ๐๐ง ๐ฆ๐๐๐ข๐๐ข๐ง๐๐ฅ ๐ฉ๐ซ๐จ๐๐ฎ๐๐ญ๐ฌ - ๐๐๐๐๐ ๐ก๐๐ข๐๐ฉ๐จ ๐๐ฅ๐ฅ๐ก๐ฎ ๐๐ค๐ง ๐ฃ๐๐ฉ๐ง๐ค๐จ๐๐ข๐๐ฃ๐๐จ ๐๐ฃ ๐ข๐๐๐๐๐๐ฃ๐๐ก ๐ฅ๐ง๐ค๐๐ช๐๐ฉ๐จ?
But what you did not know is about the insightful conversation we are hosting here in the Nitrosamine Exchange about the update. Even graphics examples have been generated to illustrate the guidanceโs ranking framework!
Kudos to our community members @Yosukemino @Pradpharma @sushantkamath @David and @lucas10mauriz for driving the whole discussion about the guidance over the weekend as soon as the update got published!
This week, the industry is meeting EMAโs Nitrosamine Implementation oversight group (NIOG) to discuss the guidance, and Iโm sure additional details will also emerge from this meeting.
Stay tuned and share any insight!
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Of course @Naiffer_Host.
Back of an envelope scribblings at the moment, but will pull together something a little more explanatory tomorrow and share.
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Thanks for sharing! This post and all of the conversation that has been shared by others is very helpful to inform others of these very important changes.
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It is worth noting that while this is great progress, the CPCA categories are still quite conservative (which is acknowledged by EMA) and read-across might provide a more appropriate basis for an AI. For example, EMA has an AI of 78,000 ng/d for nitroso-mefenamic acid based on read-across from nitroso-diphenylamine. If they used a CPCA-derived AI rather than read-across, the limit would be 1500 ng/day (52-fold lower). Itโs important to continue to have the flexibility to use read-across when it can be justified, so hopefully a CPCA-derived AI is treated as a refined default (analogous to a tiered TTC approach) and not a firmly established AI.
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Dear @David
Thank you for your helpful and informative explanation. Of course, I remember you helped us in this community many times. And I want to illustrate your explanation to understand nitrosamines deeply.
If the most-hindered side is CH2, then whether the right-hand side is CH2 or CH3 makes little difference, both sides can react and highly-reactive diazonium ions can form, hence the score of 1 - reflected in a number of potent carcinogens that match this unhindered pattern.
Isopropyl groups, as I have been saying for a number of years, lead to a dramatic reduction in potency, hence the score of 3 for either (1,3) or (1,2).
Aryl groups are interesting, because there are a few potent examples such as nitrosomethyl aniline (NMA or NMPA) which explains the lower score for (0,3), and ethyl groups are just as reactive as methyl hence the exception in (0,2). All other groups (other than activating groups) are less labile, making the rest of (0,2) have a score of 3. These also have some potential alternative mechanisms not available to the isopropyl ones, hence the lower scores for NMA and nitrosoethylaniline and ring-substituted derivatives.
As a caveat, tert-butyl groups [(0,0) (0,1), (0,2), (0,3) where the 0 is sp3], as well as the fully-hindered (0,1) and (1,1) have an effective CPCA score of >5, enough to make them category 4 if they did need the CPCA but of course donโt need it, and the only (3,3) is NDMA - which of course has a compound-specific limit. This is why not all permutations are in the CPCA.
If I made a mistake, please point it out.
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