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Novel BACE1 inhibitors with a non-acidic heterocycle at the P1′ position |
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| Authors: | Kenji Suzuki Yoshio Hamada Jeffrey-Tri Nguyen Yoshiaki Kiso |
| Institution: | 1. Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science and 21st Century COE Program, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan;2. Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Minatojima, Chuo-ku, Kobe 650-8586, Japan;3. Laboratory of Peptide Science, Nagahama Institute of Bio-Science and Technology, Tamura-cho, Nagahama 526-0829, Japan |
| Abstract: | We have reported potent peptidic and non-peptidic BACE1 inhibitors with a hydroxymethylcarbonyl (HMC) isostere as a substrate transition-state mimic. However, our potent inhibitors possess a tetrazole ring at the P1′ position. It is desirable that central nervous system (CNS) drugs do not possess an acidic moiety. In this study, we synthesized non-acidic BACE1 inhibitors with heterocyclic derivatives at the P1′ position. KMI-1764 (27) exhibited potent inhibitory activity (IC50 = 27 nM). Interestingly, these non-acidic inhibitors tended to follow the quantitative structure–activity relationship (QSAR) equation and interacted with BACE1-Arg235 in the binding model. |
| Keywords: | Non-acidic inhibitor β-Secretase Alzheimer’s disease Quantitative structure–activity relationship Hydroxymethylcarbonyl isostere |
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