- Discovery and initial optimization of 5,5′-disubstituted aminohydantoins as potent β-secretase (BACE1) inhibitors
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8,8-Diphenyl-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine (1) was identified through HTS, as a weak (micromolar) inhibitor of BACE1. X-Ray crystallographic studies indicate the 2-aminoimidazole ring forms key H-bonding interactions with Asp32 and Asp228 in the catalytic site of BACE1. Lead optimization using structure-based focused libraries led to the identification of low nanomolar BACE1 inhibitors such as 20b with substituents which extend from the S1 to the S3 pocket.
- Nowak, Pawel,Cole, Derek C.,Aulabaugh, Ann,Bard, Jonathan,Chopra, Rajiv,Cowling, Rebecca,Fan, Kristi Y.,Hu, Baihua,Jacobsen, Steve,Jani, Minakshi,Jin, Guixan,Lo, Mei-Chu,Malamas, Michael S.,Manas, Eric S.,Narasimhan, Rani,Reinhart, Peter,Robichaud, Albert J.,Stock, Joseph R.,Subrath, Joan,Svenson, Kristine,Turner, Jim,Wagner, Erik,Zhou, Ping,Ellingboe, John W.
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scheme or table
p. 632 - 635
(2010/06/12)
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- CYCLOALKYL AMINO-HYDANTOIN COMPOUNDS AND USE THEREOF FOR BETA-SECRETASE MODULATION
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The present invention provides a 2-amino-5-cycloalkyl-hydantoin compound of formula I The present invention also provides methods and compositions for the inhibition of β-secretase (BACE) and the treatment of β-amyloid deposits and neurofibrillary tangles.
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Page/Page column 24
(2010/11/25)
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