title: Pharmacological characterization of a novel liver X receptor agonist with partial LXRα activity and a favorable window in nonhuman primates.
abstract: Liver X Receptors (LXRs) α and β are nuclear hormone receptors that regulate multiple genes involved in reverse cholesterol transport (RCT) and are potential drug targets for atherosclerosis. However, full pan agonists also activate lipogenic genes, resulting in elevated plasma and hepatic lipids. We report the pharmacology of BMS-779788 [2-(2-(1-(2-chlorophenyl)-1-methylethyl)-1-(3'-(methylsulfonyl)-4-biphenylyl)-1H-imidazol-4-yl)-2-propanol], a potent partial LXR agonist with LXRβ selectivity, which has an improved therapeutic window in the cynomolgus monkey compared with a full pan agonist. BMS-779788 induced LXR target genes in blood in vivo with an EC50 = 610 nM, a value similar to its in vitro blood gene induction potency. BMS-779788 was 29- and 12-fold less potent than the full agonist T0901317 in elevating plasma triglyceride and LDL cholesterol, respectively, with similar results for plasma cholesteryl ester transfer protein and apolipoprotein B. However, ABCA1 and ABCG1 mRNA inductions in blood, which are critical for RCT, were comparable. Increased liver triglyceride was observed after 7-day treatment with BMS-779788 at the highest dose tested and was nearly identical to the dose response for plasma triglyceride, consistent with the central role of liver LXR in these lipogenic effects. Dose-dependent increases in biliary cholesterol and decreases in phospholipid and bile acid occurred in BMS-779788-treated animals, similar to LXR agonist effects reported in mouse. In summary, BMS-779788, a partial LXRβ selective agonist, has decreased lipogenic potential compared with a full pan agonist in cynomolgus monkeys, with similar potency in the induction of genes known to stimulate RCT. This provides support in nonhuman primates for improving LXR agonist therapeutic windows by limiting LXRα activity.
authors.affiliation: Bristol-Myers Squibb Research and Development, Bristol-Myers Squibb, Inc., Princeton, New Jersey (T.G.K., P.S., D.G., X.L., J.L., J.S., R.N., J.O., G.H.C., E.K.); and Exelixis, Inc., South San Francisco, California (R.Ma., Y.X., R.Mo.) tgkakm@gmail.com.
authors.forename: Todd G
authors.initials: TG
authors.lastname: Kirchgessner
authors.affiliation: Bristol-Myers Squibb Research and Development, Bristol-Myers Squibb, Inc., Princeton, New Jersey (T.G.K., P.S., D.G., X.L., J.L., J.S., R.N., J.O., G.H.C., E.K.); and Exelixis, Inc., South San Francisco, California (R.Ma., Y.X., R.Mo.).
authors.forename: Richard
authors.initials: R
authors.lastname: Martin
authors.affiliation: Bristol-Myers Squibb Research and Development, Bristol-Myers Squibb, Inc., Princeton, New Jersey (T.G.K., P.S., D.G., X.L., J.L., J.S., R.N., J.O., G.H.C., E.K.); and Exelixis, Inc., South San Francisco, California (R.Ma., Y.X., R.Mo.).
authors.forename: Paul
authors.initials: P
authors.lastname: Sleph
authors.affiliation: Bristol-Myers Squibb Research and Development, Bristol-Myers Squibb, Inc., Princeton, New Jersey (T.G.K., P.S., D.G., X.L., J.L., J.S., R.N., J.O., G.H.C., E.K.); and Exelixis, Inc., South San Francisco, California (R.Ma., Y.X., R.Mo.).
authors.forename: Denise
authors.initials: D
authors.lastname: Grimm
authors.affiliation: Bristol-Myers Squibb Research and Development, Bristol-Myers Squibb, Inc., Princeton, New Jersey (T.G.K., P.S., D.G., X.L., J.L., J.S., R.N., J.O., G.H.C., E.K.); and Exelixis, Inc., South San Francisco, California (R.Ma., Y.X., R.Mo.).
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Bristol-Myers Squibb Research and Development, Bristol-Myers Squibb, Inc., Princeton, New Jersey (T.G.K., P.S., D.G., X.L., J.L., J.S., R.N., J.O., G.H.C., E.K.); and Exelixis, Inc., South San Francisco, California (R.Ma., Y.X., R.Mo.).
authors.forename: John
authors.initials: J
authors.lastname: Lupisella
authors.affiliation: Bristol-Myers Squibb Research and Development, Bristol-Myers Squibb, Inc., Princeton, New Jersey (T.G.K., P.S., D.G., X.L., J.L., J.S., R.N., J.O., G.H.C., E.K.); and Exelixis, Inc., South San Francisco, California (R.Ma., Y.X., R.Mo.).
authors.forename: James
authors.initials: J
authors.lastname: Smalley
authors.affiliation: Bristol-Myers Squibb Research and Development, Bristol-Myers Squibb, Inc., Princeton, New Jersey (T.G.K., P.S., D.G., X.L., J.L., J.S., R.N., J.O., G.H.C., E.K.); and Exelixis, Inc., South San Francisco, California (R.Ma., Y.X., R.Mo.).
authors.forename: Rangaraj
authors.initials: R
authors.lastname: Narayanan
authors.affiliation: Bristol-Myers Squibb Research and Development, Bristol-Myers Squibb, Inc., Princeton, New Jersey (T.G.K., P.S., D.G., X.L., J.L., J.S., R.N., J.O., G.H.C., E.K.); and Exelixis, Inc., South San Francisco, California (R.Ma., Y.X., R.Mo.).
authors.forename: Yinong
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Bristol-Myers Squibb Research and Development, Bristol-Myers Squibb, Inc., Princeton, New Jersey (T.G.K., P.S., D.G., X.L., J.L., J.S., R.N., J.O., G.H.C., E.K.); and Exelixis, Inc., South San Francisco, California (R.Ma., Y.X., R.Mo.).
authors.forename: Jacek
authors.initials: J
authors.lastname: Ostrowski
authors.affiliation: Bristol-Myers Squibb Research and Development, Bristol-Myers Squibb, Inc., Princeton, New Jersey (T.G.K., P.S., D.G., X.L., J.L., J.S., R.N., J.O., G.H.C., E.K.); and Exelixis, Inc., South San Francisco, California (R.Ma., Y.X., R.Mo.).
authors.forename: Glenn H
authors.initials: GH
authors.lastname: Cantor
authors.affiliation: Bristol-Myers Squibb Research and Development, Bristol-Myers Squibb, Inc., Princeton, New Jersey (T.G.K., P.S., D.G., X.L., J.L., J.S., R.N., J.O., G.H.C., E.K.); and Exelixis, Inc., South San Francisco, California (R.Ma., Y.X., R.Mo.).
authors.forename: Raju
authors.initials: R
authors.lastname: Mohan
authors.affiliation: Bristol-Myers Squibb Research and Development, Bristol-Myers Squibb, Inc., Princeton, New Jersey (T.G.K., P.S., D.G., X.L., J.L., J.S., R.N., J.O., G.H.C., E.K.); and Exelixis, Inc., South San Francisco, California (R.Ma., Y.X., R.Mo.).
authors.forename: Ellen
authors.initials: E
authors.lastname: Kick
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000097:blood / Q000235:genetics; D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D054333:Drug Partial Agonism; D007093:Imidazoles / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D008055:Lipids / Q000097:blood; D050155:Lipogenesis / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D000071518:Liver X Receptors; D008252:Macaca fascicularis; D008297:Male; D057093:Orphan Nuclear Receptors / Q000819:agonists*; D013450:Sulfones / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; 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; D018528:ATP-Binding Cassette Transporters; D000924:Anticholesteremic Agents; D007093:Imidazoles; D008055:Lipids; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D013450:Sulfones; D014280:Triglycerides