Peroxisome proliferator-activated receptor ␥ (PPAR␥) coactivator 1␣ (PGC-1␣) is a transcriptional coactivator that is a key component in the regulation of energy production and utilization in metabolic tissues. Recent work has identified PGC-1␣ as a strong coactivator of the orphan nuclear receptor estrogen-related receptor ␣ (ERR␣), implicating ERR␣ as a potential mediator of PGC-1␣ action. To understand the role of ERR␣ in PGC-1␣ signaling, a parallel approach of high-throughput screening and gene-expression analysis was used to identify ERR␣ small-molecule regulators and target genes. We report here the identification of a potent and selective ERR␣ inverse agonist that interferes effectively with PGC-1␣͞ERR␣-dependent signaling. This inverse agonist inhibits the constitutive activity of ERR␣ in both biochemical and cell-based assays. Also, we demonstrate that monoamine oxidase B is an ERR␣ target gene whose expression is regulated by PGC-1␣ and ERR␣ and inhibited by the ERR␣ inverse agonist. The discovery of potent and selective ERR␣ modulators and their effect on PGC-1␣ signaling provides mechanistic insight into gene regulation by PGC-1␣. These findings validate ERR␣ as a promising therapeutic target in the treatment of metabolic disorders, including diabetes and obesity.

The development of LXR agonists for the treatment of coronary artery disease has been challenged by undesirable properties in animal models. Here we show the effects of an LXR agonist on lipid and lipoprotein metabolism and neutrophils in human subjects. BMS-852927, a novel LXRβ-selective compound, had favorable profiles in animal models with a wide therapeutic index in cynomolgus monkeys and mice. In healthy subjects and hypercholesterolemic patients, reverse cholesterol transport pathways were induced similarly to that in animal models. However, increased plasma and hepatic TG, plasma LDL-C, apoB, apoE, and CETP and decreased circulating neutrophils were also evident. Furthermore, similar increases in LDL-C were observed in normocholesterolemic subjects and statin-treated patients. The primate model markedly underestimated human lipogenic responses and did not predict human neutrophil effects. These studies demonstrate both beneficial and adverse LXR agonist clinical responses and emphasize the importance of further translational research in this area.

The estrogen-related receptor alpha (ERRalpha) is an orphan receptor belonging to the nuclear receptor superfamily. The physiological role of ERRalpha has yet to be established primarily because of lack of a natural ligand. Herein, we describe the discovery of the first potent and selective inverse agonist of ERRalpha. Through in vitro and in vivo studies, these ligands will elucidate the endocrine signaling pathways mediated by ERRalpha including association with human disease states.

Azepino[4,5-b]indoles have been identified as potent agonists of the farnesoid X receptor (FXR). In vitro and in vivo optimization has led to the discovery of 6m (XL335, WAY-362450) as a potent, selective, and orally bioavailable FXR agonist (EC(50) = 4 nM, Eff = 149%). Oral administration of 6m to LDLR(-/-) mice results in lowering of cholesterol and triglycerides. Chronic administration in an atherosclerosis model results in significant reduction in aortic arch lesions.

The 5-HTic receptor was first characterized by Pazos1 in 1984. It is present in high levels in the choroid plexus epithelial cells with at least 10-fold lower densities in other brain regions of both rat2 and humans3•4 and is linked to the phosphatidyl inositol hydrolysis secondary messenger system5•6 as is the 5-HT2 receptor.5•7 In addition to sharing the same secondary messenger system, both the 5-HTic and 5-HT2 receptors have similar gene sequences with 79% homology in the seven transmembrane domains in rat8 and 80% in humans.9 This accounts for the very similar pharmacological profile of both receptors. Thus most of the "classical" 5-HT receptor antagonists such as methysergide, metergoline, mianserin, and cyproheptadine have similar affinities for both receptors, while some, such as spiperone, ketanserin, and pirenperone, are 5-HT2 selective.7 Only two antagonists have been reported to show modest 5-HTic receptor selectivity compared with the 5-HT2 site: 1-naphthylpiperazine (1-NP) and LY 53857 (10-and 5-fold, respectively).7 The former compound * To whom correspondence should be addressed.