title: Discovery of Highly Potent Liver X Receptor β Agonists.
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 agonist15. The addition of polarity to the phenyl sulfone also reduced binding to the plasma protein, human α-1-acid glycoprotein. Agonist15was selected for clinical development based on the favorable combination ofin vitroproperties, excellent pharmacokinetic parameters, and a favorable lipid profile.
authors.affiliation: 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.
authors.forename: Ellen K
authors.initials: EK
authors.lastname: Kick
authors.affiliation: Exelixis Inc. , 210 East Grand Avenue, South San Francisco, California 94080, United States.
authors.forename: Brett B
authors.initials: BB
authors.lastname: Busch
authors.affiliation: Exelixis Inc. , 210 East Grand Avenue, South San Francisco, California 94080, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Martin
authors.affiliation: Exelixis Inc. , 210 East Grand Avenue, South San Francisco, California 94080, United States.
authors.forename: William C
authors.initials: WC
authors.lastname: Stevens
authors.affiliation: Exelixis Inc. , 210 East Grand Avenue, South San Francisco, California 94080, United States.
authors.forename: Venkataiah
authors.initials: V
authors.lastname: Bollu
authors.affiliation: Exelixis Inc. , 210 East Grand Avenue, South San Francisco, California 94080, United States.
authors.forename: Yinong
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Exelixis Inc. , 210 East Grand Avenue, South San Francisco, California 94080, United States.
authors.forename: Brant C
authors.initials: BC
authors.lastname: Boren
authors.affiliation: Exelixis Inc. , 210 East Grand Avenue, South San Francisco, California 94080, United States.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Nyman
authors.affiliation: Exelixis Inc. , 210 East Grand Avenue, South San Francisco, California 94080, United States.
authors.forename: Max H
authors.initials: MH
authors.lastname: Nanao
authors.affiliation: Exelixis Inc. , 210 East Grand Avenue, South San Francisco, California 94080, United States.
authors.forename: Lam
authors.initials: L
authors.lastname: Nguyen
authors.affiliation: Exelixis Inc. , 210 East Grand Avenue, South San Francisco, California 94080, United States.
authors.forename: Artur
authors.initials: A
authors.lastname: Plonowski
authors.affiliation: Exelixis Inc. , 210 East Grand Avenue, South San Francisco, California 94080, United States.
authors.forename: Ira G
authors.initials: IG
authors.lastname: Schulman
authors.affiliation: Exelixis Inc. , 210 East Grand Avenue, South San Francisco, California 94080, United States.
authors.forename: Grace
authors.initials: G
authors.lastname: Yan
authors.affiliation: 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.
authors.forename: Huiping
authors.initials: H
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Hou
authors.affiliation: 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.
authors.forename: Meriah N
authors.initials: MN
authors.lastname: Valente
authors.affiliation: 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.
authors.forename: Rangaraj
authors.initials: R
authors.lastname: Narayanan
authors.affiliation: 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.
authors.forename: Kamelia
authors.initials: K
authors.lastname: Behnia
authors.affiliation: 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.
authors.forename: A David
authors.initials: AD
authors.lastname: Rodrigues
authors.affiliation: 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.
authors.forename: Barry
authors.initials: B
authors.lastname: Brock
authors.affiliation: 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.
authors.forename: James
authors.initials: J
authors.lastname: Smalley
authors.affiliation: 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.
authors.forename: Glenn H
authors.initials: GH
authors.lastname: Cantor
authors.affiliation: 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.
authors.forename: John
authors.initials: J
authors.lastname: Lupisella
authors.affiliation: 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.
authors.forename: Paul
authors.initials: P
authors.lastname: Sleph
authors.affiliation: 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.
authors.forename: Denise
authors.initials: D
authors.lastname: Grimm
authors.affiliation: 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.
authors.forename: Jacek
authors.initials: J
authors.lastname: Ostrowski
authors.affiliation: 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.
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Wexler
authors.affiliation: 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.
authors.forename: Todd
authors.initials: T
authors.lastname: Kirchgessner
authors.affiliation: Exelixis Inc. , 210 East Grand Avenue, South San Francisco, California 94080, United States.
authors.forename: Raju
authors.initials: R
authors.lastname: Mohan
keywords: ABCA1; ABCG1; LXRα; LXRβ; Liver X receptor; α-1-acid glycoprotein