Discovery of tetrahydro-cyclopenta[b]indole as selective LXRs modulator.
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.
Ratni
Hassen
H
F. Hoffmann-La Roche Ltd, Pharmaceuticals Division, Preclinical Research, CH-4070 Basel, Switzerland.
Blum-Kaelin
Denise
D
Dehmlow
Henrietta
H
Hartman
Peter
P
Jablonski
Philippe
P
Masciadri
Raffaello
R
Maugeais
Cyrille
C
Patiny-Adam
Angelique
A
Panday
Narendra
N
Wright
Matthew
M
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
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