Hom Roy K, Gailunas Andrea F, Mamo Shumeye, Fang Larry Y, Tung Jay S, Walker Donald E, Davis David, Thorsett Eugene D, Jewett Nancy E, Moon Joseph B, John Varghese
Elan, 800 Gateway Boulevard, South San Francisco, California 94080, USA.
J Med Chem. 2004 Jan 1;47(1):158-64. doi: 10.1021/jm0304008.
The hydroxyethylene (HE) transition state isostere was developed as a scaffold to provide potent, small molecule inhibitors of human beta-secretase (BACE). The previous work on the statine series proved critical to the discovery of HE structure-activity relationships. Compound 20 with the N-terminal isophthalamide proved to be the most potent HE inhibitor (IC(50) = 30 nM) toward BACE. Unlike the statine series, we identified HE inhibitors without carboxylic acids on the C terminus, leading to enhanced cell penetration and making them attractive candidates for further drug development in Alzheimer's disease.
羟乙烯（HE）过渡态电子等排体被开发作为一种支架，以提供强效的人β-分泌酶（BACE）小分子抑制剂。之前关于他汀系列的研究对发现HE结构-活性关系至关重要。具有N-末端间苯二甲酰胺的化合物20被证明是对BACE最有效的HE抑制剂（IC(50)=30 nM）。与他汀系列不同，我们鉴定出在C末端没有羧酸的HE抑制剂，这导致细胞渗透性增强，使其成为阿尔茨海默病进一步药物开发的有吸引力的候选物。
