Submission: PET-UNK-df7eb4e6

PET-UNK-df7eb4e6

Molecule(s):

PET-UNK-df7eb4e6-1

CNC(=O)CN1Cc2ccc(Cl)cc2[C@@]2(CCN(c3cncc4sccc34)C2=O)C1

3-aminopyridine-like Check Availability on Manifold View

PET-UNK-df7eb4e6-2

CNC(=O)CN1Cc2ccc(Cl)cc2[C@@]2(CC(=O)N(c3cncc4sccc34)C2=O)C1

3-aminopyridine-like Check Availability on Manifold View

PET-UNK-df7eb4e6-3

N#CC1(CS(=O)(=O)N2Cc3ccc(Cl)cc3[C@@]3(CCN(c4cncc5sccc45)C3=O)C2)CC1

3-aminopyridine-like Check Availability on Manifold View

PET-UNK-df7eb4e6-4

N#CC1(CS(=O)(=O)N2Cc3ccc(Cl)cc3[C@@]3(CC(=O)N(c4cncc5sccc45)C3=O)C2)CC1

3-aminopyridine-like Check Availability on Manifold View

PET-UNK-df7eb4e6-5

CNC(=O)CN1Cc2ccc(Cl)cc2C2(CCN(c3cncc4sccc34)C2=O)C1

3-aminopyridine-like Check Availability on Manifold View

PET-UNK-df7eb4e6-6

CNC(=O)CN1Cc2ccc(Cl)cc2C2(CC(=O)N(c3cncc4sccc34)C2=O)C1

3-aminopyridine-like Check Availability on Manifold View

PET-UNK-df7eb4e6-7

N#CC1(CS(=O)(=O)N2Cc3ccc(Cl)cc3C3(CCN(c4cncc5sccc45)C3=O)C2)CC1

3-aminopyridine-like Check Availability on Manifold View

PET-UNK-df7eb4e6-8

N#CC1(CS(=O)(=O)N2Cc3ccc(Cl)cc3C3(CC(=O)N(c4cncc5sccc45)C3=O)C2)CC1

3-aminopyridine-like Check Availability on Manifold View

Design Rationale:

The four designs in this submission replace the P1 isoquinoline with 7-azabenzothiazole. This structural transformation leads to a slight increase in potency for the parent 3-chlorophenylacetamide (IC50 values for JIN-POS-6dc588a4-22 and ADA-UCB-6c2cb422-1 are 0.4 and 0.7 respectively). While 7-azabenzothiazole is still potentially vulnerable to metabolism, it is possible that turnover will be slower than for isoquinoline. The racemates for the designs have been included in this submission.

Other Notes:

Protein-ligand complexes (P1788 A chain) were energy-minimized using Szybki (MMFF94S). The PDB file associated with this submission contains the following: [1] P1788 A chain protein structure [2] P1788 A chain crystallographic ligand (MAT-POS-dc2604c4-1) [3-6] Binding modes predicted for Designs 1-4.