Discovery of Highly Potent Liver X Receptor β Agonists

ACS Med Chem Lett. 2016 Oct 23;7(12):1207-1212. doi: 10.1021/acsmedchemlett.6b00234.

Ellen K Kick ¹, Brett B Busch ², Richard Martin ², William C Stevens ², Venkataiah Bollu ², Yinong Xie ², Brant C Boren ², Michael C Nyman ², Max H Nanao ², Lam Nguyen ², Artur Plonowski ², Ira G Schulman ², Grace Yan ², Huiping Zhang ¹, Xiaoping Hou ¹, Meriah N Valente ¹, Rangaraj Narayanan ¹, Kamelia Behnia ¹, A David Rodrigues ¹, Barry Brock ¹, James Smalley ¹, Glenn H Cantor ¹, John Lupisella ¹, Paul Sleph ¹, Denise Grimm ¹, Jacek Ostrowski ¹, Ruth R Wexler ¹, Todd Kirchgessner ¹, Raju Mohan ²

Affiliations

1 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.
2 Exelixis Inc. , 210 East Grand Avenue, South San Francisco, California 94080, United States.

PMID: 27994765 DOI: 10.1021/acsmedchemlett.6b00234

Abstract

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.

Keywords

ABCA1; ABCG1; LXRα; LXRβ; Liver X receptor; α-1-acid glycoprotein.

Name
Email *

	Sorry, but the email address you supplied was invalid.