Brain penetrant liver X receptor (LXR) modulators based on a 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole core

[Display omitted] 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 a...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2016-10, Vol.26 (20), p.5044-5050
Hauptverfasser:	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.
Format:	Artikel
Sprache:	eng
Schlagworte:	Alzheimer’s disease Animals ATP Binding Cassette Transporter 1 - genetics ATP Binding Cassette Transporter 1 - metabolism Brain Brain - metabolism Liver X Receptors - drug effects LXR Male Rats Rats, Sprague-Dawley RNA, Messenger - genetics Structure-Activity Relationship Structure-based drug design Up-Regulation
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Zusammenfassung:	[Display omitted] 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 compound 18 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.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2016.08.089