Let’s try CPCA Scoring!! If you want to post cases, the following PDF may be available to convert and custom. And images of compounds may be available in the visualization thread. And you can request the scoring, and then someone may help you.
Thank you for asking, @Dinkar. As we discussed in the Q&A thread, the score is determined from knowledge of SAR. The structure (2,2) is easiliy affected by CYP activation compared to (1, 2) and (1,3) due to the steric hindrance. And I guess this scoring system is validated with data in LCDB.
I add the example of NTTP(7-nitroso-3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo-[4,3- a]pyrazine) @David posted.
The AI of NTTP and NNV(nitroso-varenicline) are both calculated from the AI of NTHP by the read-across method. Though NTTP has the activating feature, NNV has no activating feature. But the score of NNV is 2, the same as that of NTTP. It’s interesting.
The score of NNV: ((2,2) for H-count = 1, In a 7-membered ring = 1, Total2, limit 100 ng/day).
NNV is actually complex to assign, because of its fused bicyclic system - the nitrosamine is both in a 6- and 7-membered ring, and in this case, per the guidance, the smaller ring takes precedence - so I would say it gets 3 points: 6-membered ring and (2,2) for hydrogen count, i.e. a limit of 400!
However with a compound-specific AI in the guidance, I assume that takes precedence, otherwise there’s a full order of magnitude to play with.
Thank you for pointing it out. Yes, you are right. The feature score for only the smallest matching
ring should be applied.
The score of NNV: ((2,2) for H-count = 1, In a 6-membered ring = 2, Total3, limit 400 ng/day).
And the current AI of 37 ng/day represents less than 10% of the AI of 400 ng/day. When CPCA becomes available on NNV, it means that varenicline is free from control for NNV. And the surrogate compound of NTHP for NNV looks controversial due to the size of the ring and the position of sp2 carbon. I anticipate the update of the AI list in the future.