title: Discovery of tetrahydro-cyclopenta[b]indole as selective LXRs modulator.
abstract: A series of tetrahydro-cyclopenta[b]indoles modulating the activity of the liver-X-receptor (LXR) were derived from a high throughput screening hit. The potency and selectivity for LXRbeta versus LXRalpha was improved. One compound, administered to wild-type mice modestly increased plasma HDL-cholesterol with no change in plasma triglycerides (TG) and reduced effects on liver TG content compared to T0901317. This novel series of LXR agonists shows promise to improve therapeutic efficacy with reduced potential to increase TG.
authors.affiliation: F. Hoffmann-La Roche Ltd, Pharmaceuticals Division, Preclinical Research, CH-4070 Basel, Switzerland.
authors.forename: Hassen
authors.initials: H
authors.lastname: Ratni
authors.forename: Denise
authors.initials: D
authors.lastname: Blum-Kaelin
authors.forename: Henrietta
authors.initials: H
authors.lastname: Dehmlow
authors.forename: Peter
authors.initials: P
authors.lastname: Hartman
authors.forename: Philippe
authors.initials: P
authors.lastname: Jablonski
authors.forename: Raffaello
authors.initials: R
authors.lastname: Masciadri
authors.forename: Cyrille
authors.initials: C
authors.lastname: Maugeais
authors.forename: Angelique
authors.initials: A
authors.lastname: Patiny-Adam
authors.forename: Narendra
authors.initials: N
authors.lastname: Panday
authors.forename: Matthew
authors.initials: M
authors.lastname: Wright
mesh_terms: D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D008076:Cholesterol, HDL / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry*; D015195:Drug Design; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008956:Models, Chemical; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry*; D013449:Sulfonamides / Q000494:pharmacology; D015533:Transcriptional Activation; D014280:Triglycerides / Q000378:metabolism; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D008076:Cholesterol, HDL; D004268:DNA-Binding Proteins; D006845:Hydrocarbons, Fluorinated; D007211:Indoles; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; D014280:Triglycerides; C000605214:Nr1h3 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides