Submission Details
Molecule(s):
CO[C@@]1(C(=O)Nc2cncc3cc(C#N)ccc23)CN(S(C)(=O)=O)Cc2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3sncc23)CN(S(C)(=O)=O)Cc2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3oncc23)CN(S(C)(=O)=O)Cc2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3cnsc23)CN(S(C)(=O)=O)Cc2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3cnoc23)CN(S(C)(=O)=O)Cc2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3sccc23)CN(S(C)(=O)=O)Cc2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3cc(C#N)ccc23)CN(S(=O)(=O)N(C)C)Cc2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3sncc23)CN(S(=O)(=O)N(C)C)Cc2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3oncc23)CN(S(=O)(=O)N(C)C)Cc2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3cnsc23)CN(S(=O)(=O)N(C)C)Cc2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3cnoc23)CN(S(=O)(=O)N(C)C)Cc2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3sccc23)CN(S(=O)(=O)N(C)C)Cc2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3cc(C#N)ccc23)CN(C(C)=O)Cc2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3sncc23)CN(C(C)=O)Cc2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3oncc23)CN(C(C)=O)Cc2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3cnsc23)CN(C(C)=O)Cc2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3cnoc23)CN(C(C)=O)Cc2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3sccc23)CN(C(C)=O)Cc2ccc(Cl)cc21
Design Rationale:
The submission consists of 18 designs based on the methoxytetrahydroisoquinoline scaffold that are intended to address potential metabolism of the P1 isoquinoline (see also notes for PET-UNK-b1ef24dc and PET-UNK-6314f867 submissions). There are 6 P1 heterocycles and these are combined with 3 substituents on the tetrahydroisoquinoline N. The first 5 P1 heterocycles in the sequence would all be expected (on the basis of reduced electron density in the non-pyridine ring) to improve metabolic stability relative to isoquinoline. However, the effects on potency from substitution of these for isoquinoline are unknown (my recommendation would be to first synthesize these as the corresponding 3-chlorophenylacetamides which are included as inspirations for the submission). The 6th P1 heterocycle in the sequence would be expected (based on the JIN-POS-6dc588a4-22/ADA-UCB-6c2cb422-1 matched molecular pair) to be equipotent with PET-UNK-29afea89-2 although the rationale for improved metabolic stability is weaker.
Other Notes:
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) [3-20] Designs 1-18