For the 8-membered ring structure with side chains shown below, would you agree that this deactivation feature should be assigned a “Yes”?
Chains of ≥5 consecutive non-hydrogen atoms (cyclic or acyclic) on both sides of an acyclic N-nitroso group, with no more than 4 atoms in each chain belonging to the same ring.
This interpretation appears to be consistent with the conclusions presented in the Zhu et al. (2023) publication that was previously shared with this forum. However, strictly speaking, the deactivating feature specifies “acyclic N-nitroso“, whereas in this case, it is a cyclic N-nitroso group.
Typically you are right and this rule ( >5 consecutive non-hydrogen atoms) cannot be applied as it is a cyclic N-nitrosogroup.
On the other hand, if you put this structure to the below software, the outcome does includes this de-activating feature and the final CPCA score is 2 (AI = 100ng/day)!!
The truth is that there is a gap in the CPCA for rings which have more than 7 atoms.
Thank you all for your insights and I greatly appreciate it. On ther other hand, as indicated in the Zhu publication, the FDA has assigned Category Potency 2 for N-Nitroso-plerixafor-1, which has a cyclin N-nitroso as well, as shown in the structure below.
well, this is getting more and more interesting…my suggestion is to check first if it is possible to develop an analytical method with spec according to AI of 18ng/day. If this is possible, i would recommend to validate this method from the 10% of this spec up to 120% of the spec according to AI of 100ng/day. In this way you would submit for the highest spec and you would be ready in case this approach being rejected.
As we have seen several times, the acceptance intakes can differentiate in the compendia lists, sometimes to stricter values.
