1022892-99-4Relevant academic research and scientific papers
NOVEL COMPOUND HAVING SECRETASE INHIBITORY ACTIVITY
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Page/Page column 20, (2010/04/25)
A novel compound represented by the formula (1) below which has β-secretase inhibitory activity, its pharmaceutically acceptable salt or a prodrug thereof. wherein Ar is a substituted or unsubstituted 5 to 6 membered mono cyclic aromatic group; R1, R2 and R3 are hydrogen atom, substituted or unsubstituted alkyl group or the like, or R2 and R3 may be taken together with the adjacent nitrogen atom and carbon atom respectively to form a 3 to 6 membered ring; R4 is C1-6 alkyl group, C1-6 alkyl group substituted by phenyl, phenylthio, or a hetero ring, or the like; A is represented by the formula below: wherein X and Y are oxygen atom, NH or sulfur atom, Z is hydrogen atom, hydroxy group which may be substituted, amino group, thiol group, or the like; and B is hydroxy group, substituted or unsubstituted amino group, substituted or unsubstituted aliphatic or aromatic amino group, or the like.
Novel non-peptidic and small-sized BACE1 inhibitors
Hamada, Yoshio,Ohta, Hiroko,Miyamoto, Naoko,Yamaguchi, Ryoji,Yamani, Abdellah,Hidaka, Koushi,Kimura, Tooru,Saito, Kazuki,Hayashi, Yoshio,Ishiura, Shoichi,Kiso, Yoshiaki
, p. 1654 - 1658 (2008/12/22)
Recently, we reported substrate-based β-secretase (BACE1) inhibitors with a hydroxymethylcarbonyl (HMC) isostere as a substrate transition-state mimic. These inhibitors showed potent BACE1 inhibitory activities (～1.2 nM IC50). In order to improve in vivo enzymatic stability and permeability across the blood-brain barrier, these penta-peptidic inhibitors would need to be further optimized. On the other hand, non-peptidic inhibitors possessing isophthalic residue at the P2 position were reported from other research groups. We selected isophthalic-type aromatic residues at the P2 position and an HMC isostere at the P1 position as lead compounds. On the basis of the design approach focused on the conformer of docked inhibitor in BACE1, we found novel non-peptidic and small-sized BACE1 inhibitors possessing a 2,6-pyridinedicarboxylic, chelidamic or chelidonic residue at the P2 position.
