Design and Synthesis of 5,5′-Disubstituted Aminohydantoins as Potent and Selective Human β-Secretase (BACE1) Inhibitors

Abstract

The identification of small molecule aminohydantoins as potent and selective human beta-secretase inhibitors is reported. These analogues exhibit low nannomolar potency for BACE1, show comparable activity in a cell-based (ELISA) assay, and demonstrate >100x selectivity for the other structurally related aspartyl proteases BACE2, cathepsinD, renin, and pepsin. On the basis of the cocrystal structure of the HTS-hit 2 in the BACE1 active site and by use of a structure-based drug design approach, we methodically explored the comparatively large binding pocket of the BACE1 enzyme and identified key interactions between the ligand and the protein that contributed to the affinity. One of the more potent compounds, (S)-55, displayed an IC(50) value for BACE1 of 10 nM and exhibited comparable cellular activity (EC(50) = 20 nM) in the ELISA assay. Acute oral administration of (S)-55 at 100 mg/kg resulted in a 69% reduction of plasma A beta(40) at 8 h in a Tg2576 mouse (p < 0.001).

Advances in the identification of β-secretase inhibitors

“…Aminohydantoin 56, in which a part of the rings of 55 is truncated, shows a 10-fold higher potency (IC 50 = 3.4 µM). Furthermore, the potent BACE1 inhibitor 57 (WY-258131, IC 50 = 10 nM) was designed by their SAR study [109][110][111][112][113][114][115][116][117][118][119][120][121][122][123][124][125][126]. However, in in vivo experiments using animal models, these inhibitors showed weak efficacy in lowering Ab levels in the brain.…”

Review of Synthesis, Biological Assay and QSAR Studies of &#946;-Secretase Inhibitors

“…Michael S. Malamas et al [68] reported the synthesis and identification of small molecule aminohydantoins as potent and selective human -secretase inhibitors (Fig. 3).…”

Synthesis and biological evaluation of novel marine-derived indole-based 1,2,4-oxadiazoles derivatives as multifunctional neuroprotective agents

“…However, the structure-activity relationship study related to 1 has not been reported yet. As our ongoing effect toward marine-derived potential neuroprotective agents, a series of phidianidine-based derivatives have been synthesized and evaluated for neuroprotective effects against amyloid-b 25-35 (Ab [25][26][27][28][29][30][31][32][33][34][35] )-, hydrogenperoxide (H 2 O 2 )-, and oxygen-glucose deprivation (OGD)-induced neurotoxicity in SH-SY5Y cells. The bioassay results indicated that some of analogs, especially 2q and 2r, exhibited good in vitro neuroprotective effects in the above three screening models.…”

“…19,20 The bioactivities of phidianidines toward diverse pharmacological targets are not surprising given their interesting structural features: (i) indole fragment is a common but important pharmacophore widely presented in numerous bioactive natural products or drugs for the CNS disorders; 21,22 (ii) the 1,2,4-oxadiazole ring system, known as an ester isostere, is present in various compounds with b-amyloid imaging function in AD and anti-oxidant activity; 23,24 (iii) meanwhile the compounds incorporating guanidine fragment also have potential application in the treatment of neurodegenerative disorders (e.g., AD) and inflammation. [25][26][27] All the above observations strongly suggested that these phidianidines might have potential value in the treatment of neurodegenerative disorders, such as AD, that stimulated our great interest in the research of their neuroprotective activity.…”