Submission Details

Design Rationale:

These designs are intended to address potential metabolism of the P2-chomane and there are three pairs (with and without methoxy configurational lock) of designs in the submission. Aza-substitution next to the chromane oxygen (Designs 1/2) would be expected to reduce metabolism of the ring while the chromane oxygen would be expected (electronegativity) to render the aza nitrogen less vulnerable to oxidative metabolism (RAL-THA-2d450e86-30 is essentially equipotent to its des-aza analog ADA-UCB-6c2cb422-1 which suggests that aza-substitution at this position is well tolerated). The other design tactics are to replace the methylene next to the chromane oxygen with sulfonyl (Designs 3/4; aryl sulfonates are much less prone to hydrolysis than their alkyl equivalents) or carbonyl (Designs 5/6) which would be expected to transform the oxygen from an electron-releasing to an electron-withdrawing entity. The sulfonyl and carbonyl oxygens of these groups are solvent exposed and would not be expected to compromise potency. I have also submitted the racemates which are likely to be the initial synthetic targets.

Other Notes:

Protein-ligand complexes (P0601 A chain) were energy-minimized using Szybki (MMFF94S) fixing the coordinates of the amide nitrogen and oxygen. The PDB file associated with this submission contains the following: [1] P0601 A chain protein structure [2] P0601 A chain crystallographic ligand ( EDJ-MED-e4b030d8-11) [3-8] Binding modes for Designs 1-6

Inspired By:

RAL-THA-2d450e86-30

PET-UNK-29afea89-2

MAT-POS-b3e365b9-1