Topic automatically created for discussing the designs at:
https://covid.postera.ai/covid/submissions/ALP-POS-6f6ae286
Hi @alphalee
Given the interest in 7-fluoroisoquinoline at P1, I’ll show how pKa measurements point to C7 as being more vulnerable than C6 to metabolic attack by CYPs. I’ll include @edgriffen @mc-robinson @Ben_DNDi (who are interested in making the P1 substituent more rugged) and @jin whose JIN-POS-6dc588a4-11 design was the first 7-fluoroisoquinoline to be synthesized.
The isoquinoline nitrogen is electron-withdrawing and exerts degrees of electronic ‘pull’ on the various carbon atoms in the pi system. All other things being equal one would expect the vulnerability of sp2 carbon to CYP-catalyzed oxidation to decrease as electrons are more strongly pulled away from it. The pKa values measured for an aminoisoquinoline regioisomer can be used to quantify the electronic ‘pull’ of the aza nitrogen on the carbon to which the amino group is attached. The pKa values of 6-aminoisoquinoline and 7-aminoisoquinoline are 7.2 and 6.2 respectively and this tells us that the aza nitrogen ‘communicates’ more effectively with C6 than C7. As such, one might expect the electronic pull of the aza nitrogen to protect C6 from metabolism to a greater extent than C7.
Thanks for the rationalisation Pete, similarly as noted in EDJ-MED-b7309adf SMARTCyp flagged C-7 metabolism as a potential issue. Latest if data on EDJ-MED-b7309adf 1 and 2 suggests we do get an extended half life.
Good to know substitution at C7 of the isoquinoline is indeed beneficial, Ed, and what is the reason for using racemic material for assessment of metabolic stability?
Hi Pete, In the short term: speed. We have a variety of P2 groups and are only just beginning to narrow down on which are preferred so we can make enantiopure intermediates in bulk. Till then it’s make-test-resolve. We know there’s the risk of racemates having potency in one isomer and stability in the other, but as, up till recently most compounds have been highly cleared in rodents, we’ve been in screening mode to find something more stable. With the latest potent & stable compounds we are resolving at enough scale to get much further down the cascade.
I guessed so, Ed, and it just adds some noise to the signal. For following up the 7-fluoro analogs, I’d be thinking of putting an electron-releasing substituent like methoxy (e.g. PET-UNK-b38839dc-19 ) or dimethylamino (e.g. PET-UNK-ee8352fa-2 ) at C6 in case the slight loss of potency resulting from fluoro at C7 is due to electron pull. Essentially, I’d be hoping to turn fixing metabolism at P1 from a twofold loss in potency into a twofold gain in potency.
I would also be keen to see 6-azabenzothiophene at P1 (e.g. MAR-UCB-fd2e172f-24 ) evaluated for metabolic stability since a small increase in potency relative to isoquinoline would be anticipated. There would be concerns (metabolic instability and potential for reactive metabolite formation) about the sulfur but I still think that it would be worth taking a look at it since the low potency of the starting points restricts the room to maneuver. While I’m not suggesting that substituted 6-azabenzothiazoles shouldn’t be made, I believe that it would be an error to assume that these will necessarily be better than the unsubstituted parent heterocycle. My view is that tethering a basic center to the 6-azabenzothiazole (e.g. MAT-POS-a2421bb6-3 ) would be asking for trouble (hERG, lysosomal accumulation…).
I would expect the oxygen of 6-azabenzofuran (e.g. MAR-UCB-fd2e172f-41 ) to be relatively non-polar and I would recommend synthesizing an example to assess potency relative to isoquinoline.