Chen Zhen, Chen Jiahui, Mast Natalia, Rong Jian, Deng Xiaoyun, Shao Tuo, Fu Hualong, Yu Qingzhen, Sun Jiyun, Shao Yihan, Josephson Lee, Collier Thomas Lee, Pikuleva Irina, Liang Steven H
Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA 02114, USA.
Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH 44106, USA.
Bioorg Med Chem Lett. 2020 May 1;30(9):127068. doi: 10.1016/j.bmcl.2020.127068. Epub 2020 Mar 6.
Cholesterol 24-hydroxylase, also known as CYP46A1 (EC 1.14.13.98), is a monooxygenase and a member of the cytochrome P450 family. CYP46A1 is specifically expressed in the brain where it controls cholesterol elimination by producing 24S-hydroxylcholesterol (24-HC) as the major metabolite. Modulation of CYP46A1 activity may affect Aβ deposition and p-tau accumulation by changing 24-HC formation, which thereafter serves as potential therapeutic pathway for Alzheimer's disease. In this work, we showcase the efficient synthesis and preliminary pharmacokinetic evaluation of a novel cholesterol 24-hydroxylase inhibitor 1 for use in positron emission tomography.
胆固醇24-羟化酶，也称为CYP46A1（EC 1.14.13.98），是一种单加氧酶，属于细胞色素P450家族。CYP46A1在大脑中特异性表达，通过产生24S-羟基胆固醇（24-HC）作为主要代谢产物来控制胆固醇的清除。调节CYP46A1活性可能通过改变24-HC的形成来影响Aβ沉积和p- tau积累，这其后可作为阿尔茨海默病的潜在治疗途径。在这项工作中，我们展示了一种用于正电子发射断层扫描的新型胆固醇24-羟化酶抑制剂1的高效合成及初步药代动力学评估。
