Submission Details
Molecule(s):
COc1cc2c(NC(=O)Cc3cccc(Cl)c3)cncc2cc1F
COc1cc2c(NC(=O)Cc3cccc(Cl)c3)cncc2cc1Cl
O=C(Nc1cncc2occc12)[C@@H]1CCOc2ccc(Cl)cc21
COc1cc2c(NC(=O)[C@@H]3CCOc4ccc(Cl)cc43)cncc2cc1F
COc1cc2c(NC(=O)[C@@H]3CCOc4ccc(Cl)cc43)cncc2cc1Cl
CS(=O)(=O)N1Cc2ccc(Cl)cc2[C@H](C(=O)Nc2cncc3occc23)C1
COc1cc2c(NC(=O)[C@@H]3CN(S(C)(=O)=O)Cc4ccc(Cl)cc43)cncc2cc1F
COc1cc2c(NC(=O)[C@@H]3CN(S(C)(=O)=O)Cc4ccc(Cl)cc43)cncc2cc1Cl
CN(C)S(=O)(=O)N1Cc2ccc(Cl)cc2[C@H](C(=O)Nc2cncc3occc23)C1
COc1cc2c(NC(=O)[C@@H]3CN(S(=O)(=O)N(C)C)Cc4ccc(Cl)cc43)cncc2cc1F
COc1cc2c(NC(=O)[C@@H]3CN(S(=O)(=O)N(C)C)Cc4ccc(Cl)cc43)cncc2cc1Cl
O=C1NC[C@@H](C(=O)Nc2cncc3occc23)c2cc(Cl)ccc21
COc1cc2c(NC(=O)[C@@H]3CNC(=O)c4ccc(Cl)cc43)cncc2cc1F
COc1cc2c(NC(=O)[C@@H]3CNC(=O)c4ccc(Cl)cc43)cncc2cc1Cl
O=C(Nc1cncc2occc12)[C@@H]1CCS(=O)(=O)c2ccc(Cl)cc21
COc1cc2c(NC(=O)[C@@H]3CCS(=O)(=O)c4ccc(Cl)cc43)cncc2cc1F
COc1cc2c(NC(=O)[C@@H]3CCS(=O)(=O)c4ccc(Cl)cc43)cncc2cc1Cl
PET-UNK-b38839dc-18
Duplicate of:
MAR-UCB-fd2e172f-41
CO[C@@]1(C(=O)Nc2cncc3occc23)CCOc2ccc(Cl)cc21
COc1cc2c(NC(=O)[C@]3(OC)CCOc4ccc(Cl)cc43)cncc2cc1F
COc1cc2c(NC(=O)[C@]3(OC)CCOc4ccc(Cl)cc43)cncc2cc1Cl
CO[C@@]1(C(=O)Nc2cncc3occc23)CN(S(C)(=O)=O)Cc2ccc(Cl)cc21
COc1cc2c(NC(=O)[C@]3(OC)CN(S(C)(=O)=O)Cc4ccc(Cl)cc43)cncc2cc1F
COc1cc2c(NC(=O)[C@]3(OC)CN(S(C)(=O)=O)Cc4ccc(Cl)cc43)cncc2cc1Cl
CO[C@@]1(C(=O)Nc2cncc3occc23)CN(S(=O)(=O)N(C)C)Cc2ccc(Cl)cc21
COc1cc2c(NC(=O)[C@]3(OC)CN(S(=O)(=O)N(C)C)Cc4ccc(Cl)cc43)cncc2cc1F
COc1cc2c(NC(=O)[C@]3(OC)CN(S(=O)(=O)N(C)C)Cc4ccc(Cl)cc43)cncc2cc1Cl
CO[C@@]1(C(=O)Nc2cncc3occc23)CNC(=O)c2ccc(Cl)cc21
COc1cc2c(NC(=O)[C@]3(OC)CNC(=O)c4ccc(Cl)cc43)cncc2cc1F
COc1cc2c(NC(=O)[C@]3(OC)CNC(=O)c4ccc(Cl)cc43)cncc2cc1Cl
CO[C@@]1(C(=O)Nc2cncc3occc23)CCS(=O)(=O)c2ccc(Cl)cc21
Design Rationale:
The designs in this submission are intended to address potential metabolic instability of the P1 isoquinoline while minimizing loss of potency. There is one isoquinoline replacement in the submission and two substituted isoquinolines in the submission and these are combined with a number of scaffolds of interest in the project. Replacement of isoquinoline with 6-azoisobenzofuran would be expected to improve metabolic stability if metabolism of isoquinoline is at C7/C8 and the structural analogy with 6-azoisobenzothiophene (replacing isoquinoline with this heterocycle leads to small increase in potency) suggests that loss of potency relative to isoquinoline should be small. Two isoquinolines substituted with methoxy at C6 and either fluoro or chloro at C7 have been included with a view to countering loss of potency that may be connected with the inductive effect (electron-withdrawing) of a C7 halogen (tactic for increasing metabolic stability of isoquinoline). My recommendation would be to synthesize PET-UNK-7f7e354d-7 (previously submitted) as well as designs 1 and 2 in the first instance. However, I have included other scaffold variations in case the design team would prefer to use these to evaluate these P1 variations.
Other Notes:
Design 18 is a resubmission of MAR-UCB-fd2e172f-41 and this has been indicated in the PDB file associated with the submission. Protein-ligand complexes (P0157 A chain) were energy-minimized using Szybki (MMFF94S; amide carbonyl O and isoquinoline N fixed at the positions of the crystallographic ligand). The PDB file associated with this submission contains the following: [1] P0157 A chain [2] P0157 A chain crystallographic ligand (PET-UNK-29afea89-2) [3] Binding mode predicted for PET-UNK-7f7e354d-7 [4-33] Binding modes predicted for designs 1-30.