A series of 4-(3-biaryl)quinolines with sulfone substituents on the terminal aryl ring (8) was prepared as potential LXR agonists. High affinity LXRbeta ligands with generally modest binding selectivi Show more
A series of 4-(3-biaryl)quinolines with sulfone substituents on the terminal aryl ring (8) was prepared as potential LXR agonists. High affinity LXRbeta ligands with generally modest binding selectivity over LXRalpha and excellent agonist potency in LXR functional assays were identified. Many compounds had LXRbeta binding IC(50) values <10 nM while the most potent had EC(50) values <1.0 nM in an ABCA1 mRNA induction assay in J774 mouse cells with efficacy comparable to T0901317. Sulfone 8a was further evaluated in LDL (-/-) mice and shown to reduce atherosclerotic lesion progression. Show less
A series of quinoline-3-carboxamide containing sulfones was prepared and found to have good binding affinity for LXRbeta and moderate binding selectivity over LXRalpha. The 8-Cl quinoline analog 33 wi Show more
A series of quinoline-3-carboxamide containing sulfones was prepared and found to have good binding affinity for LXRbeta and moderate binding selectivity over LXRalpha. The 8-Cl quinoline analog 33 with a high TPSA score, displayed 34-fold binding selectivity for LXRbeta over LXRalpha (LXRbeta IC(50)=16nM), good activity for inducing ABCA1 gene expression in a THP macrophage cell line, desired weak potency in the LXRalpha Gal4 functional assay, and low blood-brain barrier penetration in rat. Show less
A series of cinnolines/quinolines was prepared and it was found that 4-phenyl-cinnoline/quinolines with either a 2',3' or 2',5'-disubstituted benzyloxy moiety or the 1-Me-7-indole methoxy moiety on th Show more
A series of cinnolines/quinolines was prepared and it was found that 4-phenyl-cinnoline/quinolines with either a 2',3' or 2',5'-disubstituted benzyloxy moiety or the 1-Me-7-indole methoxy moiety on the meta position of the 4-phenyl ring showed good binding selectivity for LXRbeta over LXRalpha. The LXRbeta binding selective modulators displayed good activity for inducing ABCA1 gene expression in J774 macrophage cell line and poor efficacy in the LXRalpha Gal4 functional assay. 26, 37 and 41 were examined for their ability to induce SREBP-1c gene expression in Huh-7 liver cell line and they were weak partial agonists. Show less
A series of potent and binding selective LXRbeta agonists was developed using the previously reported non-selective LXR ligand WAY-254011 as a structural template. With the aid of molecular modeling, Show more
A series of potent and binding selective LXRbeta agonists was developed using the previously reported non-selective LXR ligand WAY-254011 as a structural template. With the aid of molecular modeling, it was found that 2,3-diMe-Ph, 2,5-diMe-Ph, and naphthalene substituted quinoline acetic acids (such as quinoline 33, 37, and 38) showed selectivity for LXRbeta over LXRalpha in binding assays. Show less