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 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.

Trialkyl and aryl organoboranes catalyze the polymerization of dimethylsulfoxonium methylide (1). The product of the polymerization is a tris-polymethylene organoborane. Oxidation affords linear telechelic alpha-hydroxy polymethylene. The polymer molecular weight was found to be directly proportional to the stoichiometric ratio of ylide/borane, and polydispersities as low as 1.01-1.03 have been realized. Although oligomeric polymethylene has been the most frequent synthetic target of this method, polymeric star organoboranes with molecular weights of 1.5 million have been produced. The average turnover frequency at 120 degrees C in 1,2,4,5-tetrachlorobenzene/toluene is estimated at >6 x 10(6) g of polymethylene (mol boron)(-1) h(-1). The mechanism of the polyhomologation reaction involves initial formation of a zwitterionic organoborane.ylide complex which breaks down in a rate-limiting 1,2-alkyl group migration with concomitant expulsion of a molecule of DMSO. The reaction was found to be first order in the borane catalyst and zero order in ylide. DMSO does not interfere with the reaction. The temperature dependence of the reaction rate yielded the following activation energy parameters (toluene, DeltaH(++) = 23.2 kcal/mol, DeltaS(++) = 12.6 cal deg/mol, DeltaG(++) = 19.5 kcal/mol; THF, DeltaH(++) = 26.5 kcal/mol, DeltaS(++) = 21.5 cal deg/mol, DeltaG(++) = 20.1 kcal/mol).

General strategies for the synthesis of macrocycles are quite limited. Aside from several very specialized reactions that include fragmentation of bicyclic rings, the basic approach relies on ring closure of an R,ω-difunctional linear precursor under conditions of high dilution (eq 1). 1 We report a new strategy for the synthesis of macrocycles. The approach draws upon our discovery of the polyhomologation of trialkylboranes. 2 Polyhomologation results in repetitive methylene insertions into the carbon-boron bond. When applied to boracyclanes, the reaction generates macrocyclic rings (eq 2). These macrocyclic organoboranes can be elaborated to carbocyclic rings and other derivatives.The polyhomologation reaction employs the ylide dimethylsulfoxonium methylide (1) 3 as monomer, and the polymerization is initiated by trialkylboranes. For simple trialkylboranes, all three alkyl groups on boron participate, giving rise to a star polymethylene organoborane 2 (Scheme 1). These oligomeric and polymeric organoboranes (2) are amenable to synthetic transformations that can be used to terminate the polymethylene chain with functionality. 4 For example, peroxide cleavage of the carbon-boron bonds in star 2 results in hydroxyl terminated linear polymethylene 3 in yields over 90% (Scheme 1). 2 The synthesis of macrocycles by the polyhomologation reaction requires boracycles as starting materials. These compounds are readily prepared by hydroboration of dienes. Since all three boron-carbon bonds undergo polyhomologation, we chose thexylborane 5 as the hydroborating agent. The thexyl group has been shown to exhibit a low migratory aptitude in rearrangements of organoboranes. 6 The suppressed tendency toward migration should permit exclusive

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