具有体内活性的大环肽模拟β-分泌酶（BACE-1）抑制剂。
Macrocyclic peptidomimetic beta-secretase (BACE-1) inhibitors with activity in vivo.
作者信息
Machauer Rainer, Laumen Kurt, Veenstra Siem, Rondeau Jean-Michel, Tintelnot-Blomley Marina, Betschart Claudia, Jaton Anne-Lise, Desrayaud Sandrine, Staufenbiel Matthias, Rabe Sabine, Paganetti Paolo, Neumann Ulf
机构信息
Novartis Institutes for BioMedical Research, Novartis Pharma AG, PO Box, CH-4002 Basel, Switzerland.
出版信息
Bioorg Med Chem Lett. 2009 Mar 1;19(5):1366-70. doi: 10.1016/j.bmcl.2009.01.055. Epub 2009 Jan 22.
The macrocyclic peptidic BACE-1 inhibitors 2a-c show moderate enzymatic and cellular activity. By exchange of the hydroxyethylene- to ethanolamine-transition state mimetic the peptidic character was reduced, providing the highly potent and selective inhibitor 3. Variation of the P' moiety resulted in the macrocyclic inhibitor 14. Both macrocycles show inhibition of BACE-1 in the brain of APP51/16 transgenic mice, 3 (NB-544) after intravenous and 14 (NB-533) after oral application.
大环肽类BACE-1抑制剂2a-c表现出中等的酶活性和细胞活性。通过将羟乙烯转变为乙醇胺过渡态模拟物，肽的特性得以降低，从而得到了高效且具选择性的抑制剂3。对P'部分进行变化得到了大环抑制剂14。这两种大环化合物在APP51/16转基因小鼠脑内均显示出对BACE-1的抑制作用，静脉注射后3（NB-544）起作用，口服后14（NB-533）起作用。
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