Submission Details
Molecule(s):
O=C(Nc1cncc2ccccc12)[C@@H]1CN(S(=O)(=O)CC2(Cl)CC2)C(=O)c2ccc(Cl)cc21
O=C(Nc1cncc2ccccc12)C1CN(S(=O)(=O)CC2(Cl)CC2)C(=O)c2ccc(Cl)cc21
Design Rationale:
The EDJ-MED-968bafd9 submission notes mention synthetic issues as part of the rationale the methoxycyclopropane EDJ-MED-968bafd9-1. If the corresponding alcohol is to used as an intermediate for the synthesis of EDJ-MED-968bafd9-1 by methylation the chloro analog (Design 1 of this submission) should also be synthetically accessible. A tertiary cyclopropyl chloride would be expected to be stable with respect to hydrolysis on account of the instability of cyclopropyl carbocations. Design 1 will be more lipophilic than either the methoxy or cyano analogs and would be expected to have lower aqueous solubility. Polar atoms in the pendant groups in both ALP-POS-c56c1477-3 (cyano N) and EDJ-MED-968bafd9-1 (methoxy O) are likely to make contact with non-polar regions on the protein surface so Design 1 offers a potential potency gain. Design 1 would also address potential metabolic liability associated with the methoxy group of EDJ-MED-968bafd9-1. The single design in this submission has also been submitted as a racemate.
Other Notes:
Protein-ligand complexes (P1788 A chain) were energy-minimized using Szybki (MMFF94S) fixing the coordinates of the amide nitrogen and oxygen. 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) [3-4] Binding modes predicted for ALP-POS-c56c1477-3 and EDJ-MED-968bafd9-1 [5] Binding modes predicted for Design 1.