Structure-Based Design of Selective β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors: Targeting the Flap to Gain Selectivity over BACE2 was written by Fujimoto, Kazuki;Matsuoka, Eriko;Asada, Naoya;Tadano, Genta;Yamamoto, Takahiko;Nakahara, Kenji;Fuchino, Kouki;Ito, Hisanori;Kanegawa, Naoki;Moechars, Diederik;Gijsen, Harrie J. M.;Kusakabe, Ken-ichi. And the article was included in Journal of Medicinal Chemistry in 2019.Safety of Ethyl 2-(tetrahydro-2H-pyran-4-yl)acetate This article mentions the following:
BACE1 inhibitors hold potential as agents in disease-modifying treatment for Alzheimer’s disease. BACE2 cleaves the melanocyte protein PMEL in pigment cells of the skin and eye, generating melanin pigments. This role of BACE2 implies that nonselective and chronic inhibition of BACE1 may cause side effects derived from BACE2. Herein, we describe the discovery of potent and selective BACE1 inhibitors using structure-based drug design. We targeted the flap region, where the shape and flexibility differ between these enzymes. Anal. of the cocrystal structures of an initial lead 8 prompted us to incorporate spirocycles followed by its fine-tuning, culminating in highly selective compounds 21 and 22. The structures of 22 bound to BACE1 and BACE2 revealed that a relatively high energetic penalty in the flap of the 22-bound BACE2 structure may cause a loss in BACE2 potency, thereby leading to its high selectivity. These findings and insights should contribute to responding to the challenges in exploring selective BACE1 inhibitors. In the experiment, the researchers used many compounds, for example, Ethyl 2-(tetrahydro-2H-pyran-4-yl)acetate (cas: 103260-44-2Safety of Ethyl 2-(tetrahydro-2H-pyran-4-yl)acetate).
Ethyl 2-(tetrahydro-2H-pyran-4-yl)acetate (cas: 103260-44-2) belongs to tetrahydropyran derivatives. In organic synthesis, the 2-tetrahydropyranyl group is used as a protecting group for alcohols. One classic procedure for the organic synthesis of tetrahydropyran is by hydrogenation of the 3,4-isomer of dihydropyran with Raney nickel.Safety of Ethyl 2-(tetrahydro-2H-pyran-4-yl)acetate
Referemce:
Tetrahydropyran – Wikipedia,
Tetrahydropyran – an overview | ScienceDirect Topics