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Publication Abstract from PubMed

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 LXRbeta activity (>70%) with low partial LXRalpha 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 alpha-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.

Discovery of Highly Potent Liver X Receptor beta Agonists.,Kick EK, Busch BB, Martin R, Stevens WC, Bollu V, Xie Y, Boren BC, Nyman MC, Nanao MH, Nguyen L, Plonowski A, Schulman IG, Yan G, Zhang H, Hou X, Valente MN, Narayanan R, Behnia K, Rodrigues AD, Brock B, Smalley J, Cantor GH, Lupisella J, Sleph P, Grimm D, Ostrowski J, Wexler RR, Kirchgessner T, Mohan R ACS Med Chem Lett. 2016 Oct 23;7(12):1207-1212. eCollection 2016 Dec 8. PMID:27994765^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.