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 15. The addition of polarity to the phenyl sulfone also reduced binding to the plasma protein, human α-1-acid glycoprotein. Agonist 15 was selected for clinical development based on the favorable combination of in vitro properties, excellent pharmacokinetic parameters, and a favorable lipid profile.