Benzoyl 2-methyl indoles as selective PPARγ modulators

Acton, John J.; Black, Regina M.; Jones, A. Brian; Moller, David E.; Colwell, Lawrence F.; Doebber, Thomas W.; MacNaul, Karen L.; Berger, Joel P.; Wood, Harold B.

doi:10.1016/j.bmcl.2004.10.068

Cited by 121 publications

(71 citation statements)

References 21 publications

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“…Here, we present examples of novel indole-containing SPPAR␥Ms that are structurally distinct from such ligands described previously by ourselves and others (Berger et al, 2003;Minoura et al, 2004;Acton et al, 2005;Schupp et al, 2005;Burgermeister et al, 2006). These SPPAR␥Ms were identified by their ability to bind the PPAR␥ with high affinity and to serve as potent partial agonists of the receptor in cell-based transcriptional activity assays.…”

Section: Discussionmentioning

confidence: 90%

“…Thus, Tyr473 is implicated as having an important role in the stabilization of the LBD of the receptor by the former but not the latter class of ligands. Furthermore, because Tyr473 lies within the helix 12 transcriptional activation function-2 domain that composes a section of the transcriptional coactivator binding pocket of LBD (Nolte et al, 1998;Sheu et al, 2005), the inability of SPPAR␥Ms to bind to and thereby directly stabilize this region may serve as the physical basis for the differential receptor-coactivator interactions, attenuated transcriptional activity, and resulting improved tolerability observed in preclinical species with these ligands (Kintscher et al, 2000;Berger et al, 2003;Minoura et al, 2004;Acton et al, 2005;Dropinski et al, 2005;Schupp et al, 2005).…”

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confidence: 99%

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The Differential Interactions of Peroxisome Proliferator-Activated Receptor γ Ligands with Tyr473 Is a Physical Basis for Their Unique Biological Activities

Einstein

Akiyama²,

Castriota³

et al. 2007

Mol Pharmacol

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Despite their proven antidiabetic efficacy, widespread use of peroxisome proliferator-activated receptor (PPAR)␥ agonists has been limited by adverse cardiovascular effects. To overcome this shortcoming, selective PPAR␥ modulators (SPPAR␥Ms) have been identified that have antidiabetic efficacy comparable with full agonists with improved tolerability in preclinical species. The results of structural studies support the proposition that SPPAR␥Ms interact with PPAR␥ differently from full agonists, thereby providing a physical basis for their novel activities. Herein, we describe a novel PPAR␥ ligand, SPPAR␥M2. This compound was a partial agonist in a cell-based transcriptional activity assay, with diminished adipogenic activity and an attenuated gene signature in cultured human adipocytes. X-ray cocrystallography studies demonstrated that, unlike rosiglitazone, SPPAR␥M2 did not interact with the Tyr473 residue located within helix 12 of the ligand binding domain (LBD). Instead, SPPAR␥M2 was found to bind to and activate human PPAR␥ in which the Tyr473 residue had been mutated to alanine (hPPAR␥Y473A), with potencies similar to those observed with the wild-type receptor (hPPAR␥WT). In additional studies, we found that the intrinsic binding and functional potencies of structurally distinct SPPAR␥Ms were not diminished by the Y473A mutation, whereas those of various thiazolidinedione (TZD) and non-TZD PPAR␥ full agonists were reduced in a correlative manner. These results directly demonstrate the important role of Tyr473 in mediating the interaction of full agonists but not SPPAR␥Ms with the PPAR␥ LBD, thereby providing a precise molecular determinant for their differing pharmacologies.The peroxisome proliferator-activated receptors (PPARs) ␥, ␦, and ␣ compose a nuclear receptor subfamily that modulates the transcription of a large compendium of genes encoding proteins that regulate lipid metabolism, cell differentiation, and signal transduction in a ligand-dependent manner (Berger and Moller, 2002). PPAR␥ has been shown to be a master regulator of adipogenesis and nutrient metabolism in adipocytes where it is highly expressed. Thiazolidinedione (TZD) PPAR␥ full agonists have demonstrated clinical efficacy for the treatment of type 2 diabetes mellitus (T2DM) patients . However, the use of these insulin-sensitizing agents has been restricted because of their association with several adverse effects, including

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Section: Discussionmentioning

confidence: 90%

mentioning

confidence: 99%

The Differential Interactions of Peroxisome Proliferator-Activated Receptor γ Ligands with Tyr473 Is a Physical Basis for Their Unique Biological Activities

Einstein

Akiyama²,

Castriota³

et al. 2007

Mol Pharmacol

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“…In WAT, nTZDpa produced a different in vivo expression pattern of a panel of PPAR target genes when compared to a full agonist [227]. Similarly, a series of metabolically robust N-benzyl-indole partial PPARg agonists, with either a 3-benzoyl or 3-benzisoxazoyl moiety, also produced potent glucose reduction in db/db mice and attenuated increases in heart weight and BAT mass, which are typically observed in rodents upon treatment with PPARg full agonists [233,234]. In addition, halofenate, one of the recently discovered SPPARgMs, displays the characteristics of an optimized modulator, retaining an insulin sensitization potential with minimal adipogenic activity in vitro and with less weight gain in vivo (ob/ob mouse and fa/fa Zucker rat models).…”

Section: Selective Pparg Modulators: a Better Alternative?mentioning

confidence: 97%

Fat poetry: a kingdom for PPARγ

2007

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Adipose tissue is not an inert cell mass contributing only to the storage of fat, but a sophisticated ensemble of cellular components with highly specialized and complex functions. In addition to managing the most important energy reserve of the body, it secretes a multitude of soluble proteins called adipokines, which have beneficial or, alternatively, deleterious effects on the homeostasis of the whole body. The expression of these adipokines is an integrated response to various signals received from many organs, which depends heavily on the integrity and physiological status of the adipose tissue. One of the main regulators of gene expression in fat is the transcription factor peroxisome proliferatoractivated receptor g (PPARg), which is a fatty acid-and eicosanoid-dependent nuclear receptor that plays key roles in the development and maintenance of the adipose tissue. Furthermore, synthetic PPARg agonists are therapeutic agents used in the treatment of type 2 diabetes.This review discusses recent knowledge on the link between fat physiology and metabolic diseases, and the roles of PPARg in this interplay via the regulation of lipid and glucose metabolism. Finally, we assess the putative benefits of targeting this nuclear receptor with still-to-be-identified highly selective PPARg modulators.

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“…MRL-24 is a step in this direction, as it binds to PPARg with higher affinity than rosiglitazone and blocks Ser273 phosphorylation more effectively, yet induces only 20% of the transcription of rosiglitazone. It also provides as good or better glucose correction than rosiglitazone in db/db or DIO mice while inducing less heart and body weight gain (Acton et al, 2005;Choi et al, 2010). Another recently reported ligand, SR1664 (Fig.…”

Section: B Peroxisome Proliferator-activated Receptor G Functionmentioning

confidence: 99%