强效肝脏X受体β激动剂的发现。
Discovery of Highly Potent Liver X Receptor β Agonists.
作者信息
Kick Ellen K, Busch Brett B, Martin Richard, Stevens William C, Bollu Venkataiah, Xie Yinong, Boren Brant C, Nyman Michael C, Nanao Max H, Nguyen Lam, Plonowski Artur, Schulman Ira G, Yan Grace, Zhang Huiping, Hou Xiaoping, Valente Meriah N, Narayanan Rangaraj, Behnia Kamelia, Rodrigues A David, Brock Barry, Smalley James, Cantor Glenn H, Lupisella John, Sleph Paul, Grimm Denise, Ostrowski Jacek, Wexler Ruth R, Kirchgessner Todd, Mohan Raju
机构信息
Department of Discovery Chemistry, Department of Cardiovascular Biology, Pharmaceutical Candidate Optimization, Research & Development, Bristol-Myers Squibb , P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
Exelixis Inc. , 210 East Grand Avenue, South San Francisco, California 94080, United States.
出版信息
ACS Med Chem Lett. 2016 Oct 23;7(12):1207-1212. doi: 10.1021/acsmedchemlett.6b00234. eCollection 2016 Dec 8.
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 . The addition of polarity to the phenyl sulfone also reduced binding to the plasma protein, human α-1-acid glycoprotein. Agonist was selected for clinical development based on the favorable combination of properties, excellent pharmacokinetic parameters, and a favorable lipid profile.
在一系列联苯咪唑类肝脏X受体（LXR）激动剂中引入独特取代的苯砜，可显著提高其在人全血中诱导ATP结合盒转运蛋白ABCA1和ABCG1的效力。在细胞试验中，该激动剂系列表现出强大的LXRβ活性（>70%），而LXRα激动剂活性较低（<25%），这为食蟹猴中所需的血细胞ABCG1基因诱导与激动剂引起的血浆甘油三酯适度升高之间提供了一个窗口。苯砜极性的增加也降低了其与血浆蛋白人α-1-酸性糖蛋白的结合。基于其良好的综合特性、优异的药代动力学参数和有利的血脂谱，选择该激动剂进行临床开发。
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