Brain penetrant liver X receptor (LXR) modulators based on a 2, 4, 5, 6-tetrahydropyrrolo[3, 4-c]pyrazole core. Issue 20 (15th October 2016)

• Record Type: Journal Article
• Authors: Tice, Colin M.; Noto, Paul B.; Fan, Kristi Yi; Zhao, Wei; Lotesta, Stephen D.; Dong, Chengguo; Marcus, Andrew P.; Zheng, Ya-Jun; Chen, Guozhou; Wu, Zhongren; Van Orden, Rebecca; Zhou, Jing; Bukhtiyarov, Yuri; Zhao, Yi; Lipinski, Kerri; Howard, Lamont; Guo, Joan; Kandpal, Geeta; Meng, Shi; Hardy, Andrew; Krosky, Paula; Gregg, Richard E.; Leftheris, Katerina; McKeever, Brian M.; Singh, Suresh B.; Lala, Deepak; McGeehan, Gerard M.; Zhuang, Linghang; Claremon, David A.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 20(2016)
• Page Start: 5044
• Page End: 5050
• Publication Date: 2016-10-15
• Subjects: LXR -- Structure-based drug design -- Alzheimer's disease -- Brain; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.08.089
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Liver X receptor (LXR) agonists have been reported to lower brain amyloid beta (Aβ) and thus to have potential for the treatment of Alzheimer's disease. Structure and property based design led to the discovery of a series of orally bioavailable, brain penetrant LXR agonists. Oral administration of compound18 to rats resulted in significant upregulation of the expression of the LXR target gene ABCA1 in brain tissue, but no significant effect on Aβ levels was detected.