ABSTRACT
During our ongoing efforts to develop a small molecule inhibitor targeting the beta-amyloid cleaving enzyme (BACE-1), we discovered a class of compounds bearing an aminoimidazole motif. Initial optimization led to potent compounds that have high Pgp efflux ratios. Crystal structure-aided design furnished conformationally constrained compounds that are both potent and have relatively low Pgp efflux ratios. Computational studies performed after these optimizations suggest that the introduction of the constraint enhances potency via additional hydrophobic interactions rather than conformational restriction.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Imidazoles/chemistry , Protease Inhibitors/chemistry , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Amyloid Precursor Protein Secretases/metabolism , Binding Sites , Catalytic Domain , Crystallography, X-Ray , Drug Design , Humans , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Molecular Conformation , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Protein Structure, TertiaryABSTRACT
We have developed a novel series of heteroaromatic BACE-1 inhibitors. These inhibitors interact with the enzyme in a unique fashion that allows for potent binding in a non-traditional paradigm. In addition to the elucidation of their binding profile, we have discovered a pH dependent effect on the binding affinity as a result of the intrinsic pK(a) of these inhibitors and the pH of the BACE-1 enzyme binding assay.
