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Q&A: Leveraging the Necessary Nitrogen Atom for Multiparameter Optimization in Chemical Biology and Drug Discovery

Dr. Lewis D. Pennington, Alkermes

Q: Many nice examples of C->N exchange improve chemistry/ADME properties, thanks. So, what’s the scientific rational to pick up which carbon is a candidate to be replaced?
A: The specific context is important (e.g., ligand, target, anti-target, etc.): the rationale can be hypothesis-driven in some instances and probability-driven in others (e.g., by the nitrogen scanning subtype of positional analogue scanning). Please also refer to my J Med Chem Perspectives on the necessary nitrogen atom and positional analogue scanning. 

Q: When several benzene rings, where you can introduce N atom? 
A: The specific context is important (e.g., ligand, target, anti-target, etc.): the rationale can be hypothesis-driven in some instances and probability-driven in others (e.g., by the nitrogen scanning subtype of positional analogue scanning). Please also refer to my J Med Chem Perspectives on the necessary nitrogen atom and positional analogue scanning. 

Q: Would you consider aromatic/heteroaromatic N atom in drug design approach as classical or non-classical bioisosterism? 
A: Please refer to my answer to this question in the recorded webinar that is available online. 

Q: Is there any in silico prediction for hERG activation? 
A: There are predictive models for nearly all physicochemical and pharmacological parameters. Their reliability varies and is context-specific (e.g., ligand, target, anti-target, etc.).

Q: Any thoughts on how you overcome the synthetic difficulty of using pyridines instead of benzenes? 
A: Please refer to my answer to this question in the recorded webinar that is available online. Also, leverage commercially available building blocks. 

Q: How is easy or difficult to defend ‘Atom swapping’ (N vs C) in the context of steric analogy obviousness for patentability? 
A: Most structure modifications are obvious to try, it is the resulting improvement that may provide the non-obviousness that is worthy of patentability. 

Q: Thanks for showing these examples! To me, the effect of the introduction of a nitrogen on phychem props is less surprising than the effects on potency that you showed. At the same time you mentioned that there is a 1% chance to observe these effects. What can we learn from your observations to increase the probability?
A: By leveraging hypothesis-driven drug design, for example, by considering effects on conformation and/or hydrogen bonding interactions with water molecules or HBD in key protein residues that must be satisfied. 

Q: In general, how do you compare CH->N to CH -> CF?
A: Please see my recent J Med Chem Perspective on positional analogue scanning. 

Q: How many maximum N atom could be included for drug likeness? 
A: There is no defined maximum of which I am aware. 

Q: What groove of the RNA is targeted by the small molecule in SMN? What kind of contacts? 
A: Please see the cited references for this information; the recorded webinar is available online.

Q: Great talk! What is the state of the art of predicting CYP 3A4 inhibition? If we are going to insert N into rings, it would be good to have a way of de-risking and prioritizing particular substitutions.
A: The state of the art of predicting CYP 3A4 inhibition is poor. 2-Aza-analogues are much less likely than 3-aza- or 4-aza-analogues to display CYP inhibition activity. Please see the cited references for this information; the recorded webinar is available online.

Q: We can, in a reasonably predicative fashion, install a N atom to impact ADME properties. As you mentioned that is not necessarily the case with potency. How can we more predictively install a N atom to improve potency. Can artificial intelligence play a role in the future with this? 
A: Please refer to my answer to this question in the recorded webinar that is available online.

Q: How about metal-complexing properties (e.g. Fe) of the cpds on slides 14 & 15? 
A: Please refer to my answer to this question in the recorded webinar that is available online.

Q: P18 AMG510 oral improvement: adding of N increases the solubility, and thereby increases the oral F%. Have you tested the formulation approaches to increase the solubility instead of N addition? Also, did you see permeability change after C-> N? thanks. 
A: Please refer to my answer to this question in the recorded webinar that is available online.

Q: Can we arrive at some pre-requisites or predictions on when the atomic mutation of CH to N would influence the properties of the molecule (potency, phys. chem., adme, etc.). 
A: There are predictive models for nearly all physicochemical and pharmacological parameters. Their reliability varies and is context-specific (e.g., ligand, target, anti-target, etc.).

Q: Why the preclinical candidate (structure 3, slide 16) shows optimal cell permeability with undesired parameters (higher pKa & CLogP and lower tPSA)?
A: Not sure I understand this question. Please refer the recorded webinar that is available online. 

Q: Can you summarize the key points to keep in mind as we replace CH to N in aromatic rings? Should structures remain planar after replacement? 
A: Not sure I understand this question. Please refer the recorded webinar that is available online. Please also refer to my J Med Chem Perspectives on the necessary nitrogen atom and positional analogue scanning.