Discovery of Highly Potent Liver X Receptor β Agonists
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- 作者：Ellen K. Kick ; Brett B. Busch ; Richard Martin ; William C. Stevens ; Venkataiah Bollu ; Yinong Xie ; Brant C. Boren ; Michael C. Nyman ; Max H. Nanao ; Lam Nguyen ; Artur Plonowski ; Ira G. Schulman ; Grace Yan ; Huiping Zhang ; Xiaoping Hou ; Meriah N. Valente ; Rangaraj Narayanan ; Kamelia Behnia ; A. David Rodrigues ; Barry Brock ; James Smalley ; Glenn H. Cantor ; John Lupisella ; Paul Sleph ; Denise Grimm ; Jacek Ostrowski ; Ruth R. Wexler ; Todd Kirchgessner ; Raju Mohan
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2016
- 出版时间：December 8, 2016
- 年：2016
- 卷：7
- 期：12
- 页码：1207-1212
- 全文大小：345K
- ISSN：1948-5875
文摘
Introducing a uniquely substituted phenyl sulfone into a series of biphenyl imidazole liver X receptor (LXR) agonists afforded a dramatic potency improvement for induction of ATP binding cassette transporters, ABCA1 and ABCG1, in human whole blood. The agonist series demonstrated robust LXRβ activity (>70%) with low partial LXRα agonist activity (<25%) in cell assays, providing a window between desired blood cell ABCG1 gene induction in cynomolgus monkeys and modest elevation of plasma triglycerides for agonist <b>15b>. The addition of polarity to the phenyl sulfone also reduced binding to the plasma protein, human α-1-acid glycoprotein. Agonist <b>15b> was selected for clinical development based on the favorable combination of in vitro properties, excellent pharmacokinetic parameters, and a favorable lipid profile.