Estrogen-related receptor α (ERRα) is an orphan nuclear receptor that has been functionally implicated in the regulation of energy homeostasis. Herein is described the development of diaryl ether based thiazolidenediones, which function as selective ligands against this receptor. Series optimization provided several potent analogues that inhibit the recruitment of a coactivator peptide fragment in in vitro biochemical assays (IC(50) < 150 nM) and cellular two-hybrid reporter assays against the ligand binding domain (IC(50) = 1-5 μM). A cocrystal structure of the ligand-binding domain of ERRα with lead compound 29 revealed the presence of a covalent interaction between the protein and ligand, which has been shown to be reversible. In diet-induced murine models of obesity and in an overt diabetic rat model, oral administration of 29 normalized insulin and circulating triglyceride levels, improved insulin sensitivity, and was body weight neutral. This provides the first demonstration of functional activities of an ERRα ligand in metabolic animal models.

To hold an environmental ethic is to hold that non-human beings and states of affairs in the natural world have intrinsic value. This seemingly straightforward claim has been the focus of much recent philosophical discussion of environmental issues. Its clarity is, however, illusory. The term 'intrinsic value' has a variety of senses and many arguments on en vironmental ethics suffer from a conflation of these different senses: specimen hunters for the fallacy of equivocation will find rich pickings in the area. This paper is largely the work of the underlabourer. I distinguish different senses of the concept of intrinsic value, and, relatedly, of the claim that non-human beings in the natural world have intrinsic value; I exhibit the logical relations between these claims and examine the distinct motiva tions for holding them. The paper is not however merely an exercise in con ceptual underlabouring. It also defends one substantive thesis: that while it is the case that natural entities have intrinsic value in the strongest sense of the term, i.e., in the sense of value that exists independently of human valuations, such value does not as such entail any obligations on the part of human beings. The defender of nature's intrinsic value still needs to show that such value contributes to the well-being of human agents. IThe term 'intrinsic value' is used in at least three different basic senses:(1) Intrinsic value! Intrinsic value is used as a synonym for non-instrumental value. An object has instrumental value insofar as it is a means to some other end. An object has intrinsic value if it is an end in itself. Intrinsic goods are goods that other goods are good for the sake of. It is a well rehearsed point that, under pain of an infinite regress, not everything can have only instrumental value. There must be some objects that have intrin sic value. The defender of an environmental ethic argues that among the en tities that have such non-instrumental value are non-human beings and states. It is this claim that Naess makes in defending deep ecology:The well-being of non-human life on Earth has value in itself. This value is in dependent of any instrumental usefulness for limited human purposes.1

The folding of Escherichia coli dihydrofolate reductase was examined at pH 7.8 and 15°C by using stopped-flow fluorescence and absorbance spectroscopies. The formation of a highly fluorescent intermediate occurs with relaxation times ranging between 142 and 343 msec, whereas stopped-flow absorbance spectroscopy using methotrexate binding assays shows a distinct lag phase during these time frames for the native state. The lag in absorbance kinetics and the lack of fast-track folding events indicate that the formation of this ensemble of intermediates is an obligatory step in the folding reaction.T he question of whether experimentally detectable intermediates are important in kinetic mechanisms has been a point of controversy. This question has been a matter of discussion not only among biochemists. For example, mechanistic organic chemists were involved in a fierce debate as to whether specific intermediates (i) exist and (ii) are important for particular chemical reactions (1-3). It was not until detailed kinetic studies were performed that this issue was resolved. Recently, those interested in the proteinfolding problem have been engaged in a similar debate (4). Theoretical developments have proposed the possibility of two kinds of intermediates, on-route and off-route, during the folding event (5). The on-route idea is attractive, because it allows for a way to reduce the time needed for a full conformational search by forming a population of intermediates (6). Others have shown that populated partially folded forms may impede the formation of the native state (7,8). One limitation in analysis of protein folding reactions is that many intermediates are formed within the dead time of the available instrumentation. Thus, detailed kinetic studies do not reveal the role of these ''burst-phase'' intermediates.Dihydrofolate reductase (DHFR) from Escherichia coli is a particularly amenable system with which to address the role of intermediates in the formation of native protein. The folding reaction has been studied in detail (9-11). Parallel routes in refolding proceed through the population of two classes of intermediate species. The first detectable event is the formation of a marginally stable ''burst-phase'' intermediate, with a high degree of secondary structure and an exposed hydrophobic core (12, 13). After this event, the next detectable phase occurs in a time frame of hundreds of milliseconds and characterizes an ensemble of metastable species, designated as the highly fluorescent intermediate, I HF , which contain specific tertiary contacts (10). The formation of this intermediate can be monitored easily by stoppedflow fluorescence and CD spectroscopies. Native protein is formed in parallel reactions, with relaxation times ranging from 1-100 sec. Methotrexate, a potent inhibitor of DHFR, binds to the native state but not to I HF and shows a maximum in absorbance difference at 380 nm when bound. Thus, we can monitor the formation of the inhibitor binding pocket under conditions where protein signals do not...

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