Design, Synthesis, and Qualitative Structure–Activity Evaluations of Novel β-Secretase Inhibitors as Potential Alzheimer’s Drug Leads

Abstract

We have identified highly selective imidazopyridines armed with benzimidazol and/or arylimidazole as potent β-secretase inhibitors. The most effective and selective analogues demonstrated low nanomolar potency for the BACE1 enzyme as measured by FRET and cell-based (ELISA) assays and exhibited comparable affinity (KI) and high ligand efficiency (LE). In addition, these motifs were highly selective (>200) against the structurally related aspartyl protease BACE2. Our design strategy followed a traditional SAR approach and was supported by molecular modeling studies based on the previously reported hydroxyethylene transition state inhibitor derived from isophthalic acid I. Of the most potent compounds, 34 displayed an IC50 for BACE1 of 18 nM and exhibited cellular activity with an EC50 of 37 nM in the cell-based ELISA assay, as well as high affinity (KI=17 nM) and ligand efficiency (LE=1.7 kJ/mol). Compound 34 was found to be 204-fold more selective for BACE1 compared to the closely related aspartyl protease BACE2.

Combining BACE1 Inhibition with Metal Chelation as Possible Therapy for Alzheimer’s Disease

“…4). These low molecular weight compounds demonstrated low nanomolar potency against BACE1 enzyme as measured by fluorescence resonance energy transfer and cell-based assays [30]. Furthermore, these non-peptide compounds allowed the reduction of overall molecular weight and hydrogen bond formation ability, leading to inhibitors with good BBB penetration properties while still inhibiting the BACE1 at low nanomolar levels with efficacy in reducing Aβ levels from the brain in mice.…”

Conformational Restriction: An Effective Tactic in ‘Follow-On’-Based Drug Discovery

“…To further improve the potency of BACE1 inhibitors, structure-based evolution combined with conformational constraint strategy of these lead compounds 3, 5, 7, 9 and 11 was performed to facilitate access to the prime side of the BACE1 active site, which provided the discovery of the corresponding conformationally restricted analogues (such as 3-hydroxypyrrolidine 4 [16], imidazo[1,2-a]pyridine 6 [17], pyrrolidine 8 [18], bicyclic iminopyrimidinone 10 [19] and chiral cyclopropanes 12a-c [20,21]; Figure 1). …”

“…Compound 6, in particular, exhibited BACE1 inhibitory potency with an IC 50 of 18 nM and displayed an EC 50 for cell-based ELISA assay of 37 nM, as well as high affinity (K i = 17 nM) and ligand efficiency of 1.7 kJ/mol [17]. The potency of pyrrolidine-based β-secretase inhibitor 8 was enhanced by four orders of magnitude from the high-throughput screening of lead 7 with accompanying improvement in physical properties [18].…”

Structure-activity Relationships for Bergenin Analogues as ^|^beta;-Secretase (BACE1) Inhibitors

“…To allow for the quenching effect of samples, the sample solution was added to the reaction mixture C, and any reduction in fluorescence by the sample was then investigated. IC 50 was calculated by the application of the Reed and Muench method 47 , as follows:…”