National Center for
4ZPG: Bace1 In Complex With 8-benzyl-4-(cyclohexylamino)-1-(3-fluorophenyl)- 7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one
Methyl-substitution of an iminohydantoin spiropiperidine beta-secretase (BACE-1) inhibitor has a profound effect on its potency
Bioorg. Med. Chem. Lett. (2015) 25 p.4812-4819
The IC50 of a beta-secretase (BACE-1) lead compound was improved approximately 200-fold from 11muM to 55nM through the addition of a single methyl group. Computational chemistry, small molecule NMR, and protein crystallography capabilities were used to compare the solution conformation of the ligand under varying pH conditions to its conformation when bound in the active site. Chemical modification then explored available binding pockets adjacent to the ligand. A strategically placed methyl group not only maintained the required pKa of the piperidine nitrogen and filled a small hydrophobic pocket, but more importantly, stabilized the conformation best suited for optimized binding to the receptor.