Novel non-peptidic and small-sized BACE1 inhibitors |
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Authors: | Hamada Yoshio Ohta Hiroko Miyamoto Naoko Yamaguchi Ryoji Yamani Abdellah Hidaka Koushi Kimura Tooru Saito Kazuki Hayashi Yoshio Ishiura Shoichi Kiso Yoshiaki |
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Institution: | Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science and 21st Century COE Program, Kyoto Pharmaceutical University, Kyoto 607-8412, Japan. |
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Abstract: | Recently, we reported substrate-based beta-secretase (BACE1) inhibitors with a hydroxymethylcarbonyl (HMC) isostere as a substrate transition-state mimic. These inhibitors showed potent BACE1 inhibitory activities (approximately 1.2 nM IC(50)). 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 P(2) position were reported from other research groups. We selected isophthalic-type aromatic residues at the P(2) position and an HMC isostere at the P(1) 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 P(2) position. |
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