Submission Details

Design Rationale:

Present aza nitrogen with increased hydrogen bond basicity to S1 subsite while maintaining non-coplanar orientation of heteroaromatic ring with amide.

Other Notes:

Five analogs of ADA-UCB-6c2cb422-1 for which the hydrogen bond basicity of the P1 heteroaryl nitrogen is expected to be greater than that of the isoquinoline nitrogen. In the bound conformations of compounds like this, the planes of the P1 heteroaromatic ring and amide are approximately orthogonal and so these analogs have been designed to favor this orthogonal orientation. I would anticipate an increased risk of CYP inhibition for aza nitrogen in a 5-membered ring.