918541-99-8Relevant academic research and scientific papers
Di-substituted pyridinyl aminohydantoins as potent and highly selective human β-secretase (BACE1) inhibitors
Malamas, Michael S.,Barnes, Keith,Johnson, Matthew,Hui, Yu,Zhou, Ping,Turner, Jim,Hu, Yun,Wagner, Erik,Fan, Kristi,Chopra, Rajiv,Olland, Andrea,Bard, Jonathan,Pangalos, Menelas,Reinhart, Peter,Robichaud, Albert J.
scheme or table, p. 630 - 639 (2010/04/26)
The identification of highly selective small molecule di-substituted pyridinyl aminohydantoins as β-secretase inhibitors is reported. The more potent and selective analogs demonstrate low nanomolar potency for the BACE1 enzyme as measured in a FRET assay, and exhibit comparable activity in a cell-based (ELISA) assay. In addition, these pyridine-aminohydantoins are highly selectivity (>500×) against the other structurally related aspartyl proteases BACE2, cathepsin D, pepsin and renin. Our design strategy followed a traditional SAR approach and was supported by molecular modeling studies based on the previously reported aminohydantoin 3a. We have taken advantage of the amino acid difference between the BACE1 and BACE2 at the S2′ pocket (BACE1 Pro70 changed to BACE2 Lys86) to build ligands with >500-fold selectivity against BACE2. The addition of large substituents on the targeted ligand at the vicinity of this aberration has generated a steric conflict between the ligand and these two proteins, thus impacting the ligand's affinity and selectivity. These ligands have also shown an exceptional selectivity against cathepsin D (>5000-fold) as well as the other aspartyl proteases mentioned. One of the more potent compounds (S)-39 displayed an IC50 value for BACE1 of 10 nM, and exhibited cellular activity with an EC50 value of 130 nM in the ELISA assay.
NOVEL 2-AMINO-5, 5-DIARYL-IMIDAZOL-4-ONES
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Page/Page column 230-231, (2008/12/06)
This invention relates to novel compounds having the structural formula (I) below: and to their pharmaceutically acceptable salt, compositions and methods of use. These novel compounds provide a treatment or prophylaxis of cognitive impairment, Alzheimer Disease, neurodegeneration and dementia.
