Submission Details
Molecule(s):
CO[C@@]1(C(=O)Nc2cncc3ccccc23)CCOc2c(F)cc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3cn[nH]c23)CCOc2c(F)cc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3cnn(C)c23)CCOc2c(F)cc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3sccc23)CCOc2c(F)cc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3occc23)CCOc2c(F)cc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3cc(F)ccc23)CCOc2c(F)cc(Cl)cc21
COc1cc2c(NC(=O)[C@]3(OC)CCOc4c(F)cc(Cl)cc43)cncc2cc1F
CO[C@@]1(C(=O)Nc2cncc3cc(F)c(N(C)C)cc23)CCOc2c(F)cc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3ccc(NS(C)(=O)=O)cc23)CCOc2c(F)cc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3cc(F)c(NS(C)(=O)=O)cc23)CCOc2c(F)cc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3ccc(N(C)S(C)(=O)=O)cc23)CCOc2c(F)cc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3ccc(S(C)(=O)=O)cc23)CCOc2c(F)cc(Cl)cc21
COc1cc2c(NC(=O)[C@]3(OC)CCOc4c(F)cc(Cl)cc43)cncc2cn1
COc1cc2cncc(NC(=O)[C@]3(OC)CCOc4c(F)cc(Cl)cc43)c2cn1
COC1(C(=O)Nc2cncc3ccccc23)CCOc2c(F)cc(Cl)cc21
COC1(C(=O)Nc2cncc3cn[nH]c23)CCOc2c(F)cc(Cl)cc21
COC1(C(=O)Nc2cncc3cnn(C)c23)CCOc2c(F)cc(Cl)cc21
COC1(C(=O)Nc2cncc3sccc23)CCOc2c(F)cc(Cl)cc21
COC1(C(=O)Nc2cncc3occc23)CCOc2c(F)cc(Cl)cc21
COC1(C(=O)Nc2cncc3cc(F)ccc23)CCOc2c(F)cc(Cl)cc21
COc1cc2c(NC(=O)C3(OC)CCOc4c(F)cc(Cl)cc43)cncc2cc1F
COC1(C(=O)Nc2cncc3cc(F)c(N(C)C)cc23)CCOc2c(F)cc(Cl)cc21
COC1(C(=O)Nc2cncc3ccc(NS(C)(=O)=O)cc23)CCOc2c(F)cc(Cl)cc21
COC1(C(=O)Nc2cncc3cc(F)c(NS(C)(=O)=O)cc23)CCOc2c(F)cc(Cl)cc21
COC1(C(=O)Nc2cncc3ccc(N(C)S(C)(=O)=O)cc23)CCOc2c(F)cc(Cl)cc21
COC1(C(=O)Nc2cncc3ccc(S(C)(=O)=O)cc23)CCOc2c(F)cc(Cl)cc21
COc1cc2c(NC(=O)C3(OC)CCOc4c(F)cc(Cl)cc43)cncc2cn1
COc1cc2cncc(NC(=O)C3(OC)CCOc4c(F)cc(Cl)cc43)c2cn1
Design Rationale:
The designs in this submission are based on the P2 chromane from RAL-THA-05e671eb-17 (the fluoro substituent on the P2 aromatic ring is likely to provide some protection against metabolism of this aromatic ring and may even lead to a small increase in potency since RAL-THA-2d450e86-14 is twofold more potent than ADA-UCB-6c2cb422-1). This P2 group is combined with isoquinoline (Design 1) and 12 P1 groups intended to address metabolism (primarily at C7/8) of the isoquinoline while minimizing loss of potency. Designs 2/3 (pyrazolopyridine; aza substituent likely to protect against metabolism and potency loss relative to IQ is small). Design 4 (6-azabenzothiophene: equipotent to IQ and key question is whether sulfur is more resistant to metabolism than C7/C8 of IQ). Design 5 (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 6 (7-fluoroisoquinoline blocks C7 and known to result in only a small reduction in potency) Designs 7/8 (combine electron-releasing C6 substituent with fluoro at C7 with a view to achieving small increase in potency while protecting C7/C8 from metabolism). Designs 9-11 (based on 6-methanesulfonamido substitution which does not appear to result in loss of potency). Design 12 (6-methanesulfonyl substitution which appears to provide some protection against metabolism). Designs 13/14 (methoxy naphthyridines; see design notes for submission). The racemates corresponding to these designs have been included in the submission as Designs 15-28 for the convenience of the design team.
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) [3-16] Binding modes for Designs 1-14.