Submission ALP-POS-75715966

Topic automatically created for discussing the designs at:

Hi @alphalee

You may also wish to consider removing the dimethylamino substituent of the ALP-POS-6d04362c-2 design since this will enable the contribution of this substituent to potency to be quantified.

I’d also suggest using pyridine (without the 4-methyl like in PET-UNK-55f647aa-3) as the P1 substituent. I believe that the ‘function’ of the 4-methyl substituent on pyridine in compounds such as TRY-UNI-714a760b-6 is to push the pyridine out of coplanarity with respect to the amide. A pyridine that is attached to CH2 (rather than amide NH) tends to sit naturally out of the plane of the amide group (and therefore doesn’t ‘need’ the ‘assistance’ of the methyl group).

Here’s some SAR which suggests that the potency advantage of quinoline over pyridine is smaller when the heterocycle is linked to carbonyl by CH2 than by NH. We
can compare the effects on potency of ‘reversing’ the central acetamide spacer for P1 pyridine with P1 isoquinoline. TRY-UNI-714a760b-6 and EDJ-MED-49816e9b-1 (with pyridine at P1) are very similar in potency. In contrast, ‘reversing’ the acetamide spacer of ADA-UCB-6c2cb422-1 to give PET-UNK-8922bd3c-1 results in an order of magnitude reduction in potency. I’ll also link a previous discussion in case it’s helpful.