Submission Details
Molecule(s):
CO[C@@]1(C(=O)Nc2cncc3ccc(N(C)S(C)(=O)=O)cc23)CCOc2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3cc(F)c(NS(C)(=O)=O)cc23)CCOc2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3cc(F)c(N(C)S(C)(=O)=O)cc23)CCOc2ccc(Cl)cc21
Design Rationale:
The designs in this submission are derived from EDG-MED-10fcb19e-1 (IC50 = 150 nM for racemate). The sulfonamide NH hydrogen bond donor is capped with methyl in Design 1. For secondary amides, this transformation tends to result in increased aqueous solubility (see https://doi.org/10.1016/j.bmcl.2008.12.003 ; MedChemica may have analogous data for sulfonamides) and N-methylation of EDG-MED-10fcb19e-1 also has the potential to increase potency (e.g. if binding restricts solvation of the sulfonamide NH). Design 2 substitutes with fluoro at C7 which may provide a degree of protection from metabolism. Design 3 combines Design 1 with Design 2.
Other Notes:
Protein-ligand complexes (P0157 A chain from complex with Design 1) 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] Binding mode predicted for EDG-MED-10fcb19e-1 [4-6] Binding modes predicted for Designs 1-3.