title: Liver X receptor (LXR) partial agonists: biaryl pyrazoles and imidazoles displaying a preference for LXRβ.
abstract: A series of biaryl pyrazole and imidazole Liver X Receptor (LXR) partial agonists has been synthesized displaying LXRβ selectivity. The LXRβ selective partial agonist 18 was identified with potent induction of ATP binding transporters ABCA1 and ABCG1 in human whole blood (EC50=1.2μM, 55% efficacy). In mice 18 displayed peripheral induction of ABCA1 at 3 and 10mpk doses with no significant elevation of plasma or hepatic triglycerides at these doses, showing an improved profile compared to a full pan-agonist.
authors.affiliation: Discovery Chemistry, Research & Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, United States. Electronic address: ellen.kick@bms.com.
authors.forename: Ellen
authors.initials: E
authors.lastname: Kick
authors.affiliation: Exelixis Inc, 210 East Grand Avenue, So. San Francisco, CA 94080, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Martin
authors.affiliation: Exelixis Inc, 210 East Grand Avenue, So. San Francisco, CA 94080, United States.
authors.forename: Yinong
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Exelixis Inc, 210 East Grand Avenue, So. San Francisco, CA 94080, United States.
authors.forename: Brenton
authors.initials: B
authors.lastname: Flatt
authors.affiliation: Exelixis Inc, 210 East Grand Avenue, So. San Francisco, CA 94080, United States.
authors.forename: Edwin
authors.initials: E
authors.lastname: Schweiger
authors.affiliation: Exelixis Inc, 210 East Grand Avenue, So. San Francisco, CA 94080, United States.
authors.forename: Tie-Lin
authors.initials: TL
authors.lastname: Wang
authors.affiliation: Exelixis Inc, 210 East Grand Avenue, So. San Francisco, CA 94080, United States.
authors.forename: Brett
authors.initials: B
authors.lastname: Busch
authors.affiliation: Exelixis Inc, 210 East Grand Avenue, So. San Francisco, CA 94080, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Nyman
authors.affiliation: Exelixis Inc, 210 East Grand Avenue, So. San Francisco, CA 94080, United States.
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Gu
authors.affiliation: Exelixis Inc, 210 East Grand Avenue, So. San Francisco, CA 94080, United States.
authors.forename: Grace
authors.initials: G
authors.lastname: Yan
authors.affiliation: Exelixis Inc, 210 East Grand Avenue, So. San Francisco, CA 94080, United States.
authors.forename: Brandee
authors.initials: B
authors.lastname: Wagner
authors.affiliation: Exelixis Inc, 210 East Grand Avenue, So. San Francisco, CA 94080, United States.
authors.forename: Max
authors.initials: M
authors.lastname: Nanao
authors.affiliation: Exelixis Inc, 210 East Grand Avenue, So. San Francisco, CA 94080, United States.
authors.forename: Lam
authors.initials: L
authors.lastname: Nguyen
authors.affiliation: Exelixis Inc, 210 East Grand Avenue, So. San Francisco, CA 94080, United States.
authors.forename: Thomas
authors.initials: T
authors.lastname: Stout
authors.affiliation: Exelixis Inc, 210 East Grand Avenue, So. San Francisco, CA 94080, United States.
authors.forename: Artur
authors.initials: A
authors.lastname: Plonowski
authors.affiliation: Exelixis Inc, 210 East Grand Avenue, So. San Francisco, CA 94080, United States.
authors.forename: Ira
authors.initials: I
authors.lastname: Schulman
authors.affiliation: Cardiovascular Biology, Research & Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, United States.
authors.forename: Jacek
authors.initials: J
authors.lastname: Ostrowski
authors.affiliation: Cardiovascular Biology, Research & Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, United States.
authors.forename: Todd
authors.initials: T
authors.lastname: Kirchgessner
authors.affiliation: Discovery Chemistry, Research & Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, United States.
authors.forename: Ruth
authors.initials: R
authors.lastname: Wexler
authors.affiliation: Exelixis Inc, 210 East Grand Avenue, So. San Francisco, CA 94080, United States.
authors.forename: Raju
authors.initials: R
authors.lastname: Mohan
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000097:blood*; D000818:Animals; D054333:Drug Partial Agonism; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D000071518:Liver X Receptors; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D057093:Orphan Nuclear Receptors / Q000819:agonists*; D010949:Plasma / Q000737:chemistry; D011720:Pyrazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D014018:Tissue Distribution; D014280:Triglycerides / Q000378:metabolism
chemical_list: C000596177:2-(2-(1-(2-chlorophenyl)-1-methylethyl)-1-(3'-(methylsulfonyl)-4-biphenylyl)-1H-imidazol-4-yl)-2-propanol; D064286:ATP Binding Cassette Transporter 1; D007093:Imidazoles; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D011720:Pyrazoles; D013450:Sulfones; D014280:Triglycerides
keywords: ABCA1; LXR; Liver X Receptor; Nuclear hormone receptor; Partial agonist