Submission Details

Design Rationale:

The designs in this submission combine the lactam P2 subsituent of MIC-UNK-91acba05-1 with 9 variations of the parent isoquinoline (IQ) that are intended to address potential metabolism at C7/C8 of isoquinoline while minimizing loss of potency. Each design in this submission is a methoxy analog (configurational lock) of a design in the PET-UNK-7279c968 submission. Designs 1/2 (pyrazolopyridine: aza substituent likely to protect against metabolism and potency loss relative to IQ is small). Design 3 (6-azabenzothiophene: equipotent to IQ and key question is whether sulfur is more resistant to metabolism than C7/C8 of IQ). Design 4 (6-azabenzofuran: oxygen will more resistant to metabolism than sulfur of Design 3 and key question is how much potency will be lost relative to Design 3). Design 5 (fluoro at C7 of IQ: obvious modification to block metabolism and loss of potency likely to be small). Designs 6/7 (naphthyridines: use electron-releasing substituent at C6 to counter HB basicity weakening effect of C7 aza on the nitrogen that accepts HB). Designs 8/9 (combine electron-withdrawing C6 substituent with fluoro at C7 with a view to achieving small increase in potency while protecting C7/C8 from metabolism). Submission notes for PET-UNK-f4e47ebd are relevant to current submission.

Other Notes:

Protein-ligand complexes (P0157 A chain) were energy-minimized using Szybki (MMFF94S). The PDB file associated with this submission contains the following: [1] P0157 A chain protein structure [2] P0157 A chain crystallographic ligand (PET-UNK-29afea89-2) [3-11] Designs 1-9.

Inspired By:

PET-UNK-d899bab6-3

PET-UNK-7f7e354d-7

JIN-POS-6dc588a4-22

RUB-POS-1325a9ea-12

PET-UNK-d899bab6-2

MIC-UNK-91acba05-1

PET-UNK-b38839dc-1

RUB-POS-1325a9ea-14

PET-UNK-f4e47ebd-1