Submission Details
Molecule(s):
O=C(N[C@@H](C(=O)Nc1cncc2ccccc12)c1ccc(Cl)cc1)[C@@H]1CC[C@H](C(=O)N2CCCC2)O1
O=C(N[C@H](C(=O)Nc1cncc2ccccc12)c1ccc(Cl)cc1)[C@@H]1CC[C@H](C(=O)N2CCCC2)O1
O=C(N[C@@H](C(=O)Nc1cccnc1)c1cccc(Cl)c1)[C@@H]1CC[C@H](C(=O)N2CCCC2)O1
O=C(N[C@H](C(=O)Nc1cccnc1)c1cccc(Cl)c1)[C@@H]1CC[C@H](C(=O)N2CCCC2)O1
O=C(N[C@@H](C(=O)Nc1cncc2ccccc12)c1cccc(Cl)c1)[C@H]1CC[C@H](C(=O)N2CCCC2)O1
O=C(Nc1cncc2ccccc12)[C@@H](NC(=O)[C@H]1CC[C@H](C(=O)N2CCCC2)O1)c1cccc(Cl)c1
O=C(N[C@@H](C(=O)Nc1cncc2ccccc12)c1cccc(Cl)c1)[C@@H]1CC[C@@H](C(=O)N2CCCC2)O1
O=C(N[C@H](C(=O)Nc1cncc2ccccc12)c1cccc(Cl)c1)[C@@H]1CC[C@@H](C(=O)N2CCCC2)O1
O=C(N[C@@H](C(=O)Nc1cncc2ccccc12)c1cccc(Cl)c1)[C@H]1CC[C@@H](C(=O)N2CCCC2)O1
O=C(Nc1cncc2ccccc12)[C@@H](NC(=O)[C@H]1CC[C@@H](C(=O)N2CCCC2)O1)c1cccc(Cl)c1
Design Rationale:
The observation of an EC50 (0.09 μM) for MAT-POS-a13804f0-4 that is significantly less than the IC50 values observed in the fluorescence (0.56 μM) and RapidFire (1.3 μM) assays suggests that it may be beneficial to treat the compound as if it was a hit from a phenotypic screen. This means not assuming that the enzyme inhibition SAR will necessarily transfer to the cell-based assay. The designs have been submitted pairs (alternative configurations of phenylglycine configuration [1] Designs 1/2: Replace P2 3-chlorophenyl with 4-clorophenyl [2] Designs 3/4: replace P1 isoquinoline with pyridine [3] Designs 5/6 | 7/8 | 9/10: permute configurations of tetrahydrofuran linker.
Other Notes:
Given uncertainties in binding mode and the configuration of the 3-chorophenylglycine chiral center, a PDB file has not been uploaded with this submission. I'm assuming that synthesis would be carried out using racemic phenylglycines although I have submitted separate designs for each phenylglycine enantiomer.