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Biotech / Medical : Ligand (LGND) Breakout! -- Ignore unavailable to you. Want to Upgrade?

To: Peter Singleton who wrote (22190)	6/14/1998 7:41:00 AM
From: Henry Niman	Respond to of 32384

Here's one of the clincal abstracts on Avandia: Abstract #: 0067Abstract Type: OralsAbstract Category:Oral Agents (Clinical/Therapeutics)Presentation Time:8:00-10:00 AMPresentation Date:6/14/97 Rosiglitazone (BRL49653) Monotherapy Has Significant Glucose Lowering Effect in Type 2 Diabetic Patients JAI PATEL 1, ELIZABETH MILLER 1, RITA PATWARDHAN 1THE ROSIGLITAZONE 011 STUDY GROUP, Collegeville, PA, USA. ------------------------------------------------------------------------ Rosiglitazone (RSG) is the most potent member of the thiazolidinedione class. In a multi-centre, placebo-controlled trial, 493 patients (diet failure or previously treated) with a fasting glucose between 140 and 300 mg/dL, were randomly assigned to treatment with placebo, RSG 4 mg or RSG 8 mg per day. All treatments were administered as a twice daily regimen for 26 weeks following a 4 week placebo run-in period. The efficacy results are summarized below: These results demonstrate that RSG had a clinically and highly statistically significant glucose lowering effect compared to placebo and baseline. Historical comparison with troglitazone monotherapy data (Diabetes 46:supplement (1) 43A, 1997) suggests that the greater potency of rosiglitazone in pre-clinical models appear to translate into greater anti-hyperglycemic effects in man. Overall, the proportion of patients reporting adverse experiences was comparable between the treatment groups. There was a small dose dependent decrease in hemoglobin and hematocrit. There were no serious adverse experiences related to the liver or hypoglycemia. In conclusion, rosiglitazone monotherapy has been demonstrated to be well tolerated and effective in Type 2 diabetic patients.

To: Peter Singleton who wrote (22190)	6/14/1998 10:55:00 PM
From: Henry Niman	Read Replies (1) \| Respond to of 32384

Bloomberg has come out with a very favorable report on SBH's Avandia: paradise-web.com LGD1268 and LGD1324 synergize with Avandia in mouse and rat models of type II diabetes (LGND abstracts at ADA)

To: Peter Singleton who wrote (22190)	6/15/1998 7:50:00 AM
From: Henry Niman	Read Replies (1) \| Respond to of 32384

Speaking of TZD's Ron Evans published a couple of papers in Cell fairly recently on endogenous ligands for PPARgamma. Here's one abstract: Oxidized LDL regulates macrophage gene expression through ligand activation of PPARgamma. Nagy L, Tontonoz P, Alvarez JG, Chen H, Evans RM The Salk Institute of Biological Studies, Howard Hughes Medical Institute, La Jolla, California 92037, USA. Macrophage uptake of oxidized low-density lipoprotein (oxLDL) is thought to play a central role in foam cell formation and the pathogenesis of atherosclerosis. We demonstrate here that oxLDL activates PPARgamma-dependent transcription through a novel signaling pathway involving scavenger receptor-mediated particle uptake. Moreover, we identify two of the major oxidized lipid components of oxLDL, 9-HODE and 13-HODE, as endogenous activators and ligands of PPARgamma. Our data suggest that the biologic effects of oxLDL are coordinated by two sets of receptors, one on the cell surface, which binds and internalizes the particle, and one in the nucleus, which is transcriptionally activated by its component lipids. These results suggest that PPARgamma may be a key regulator of foam cell gene expression. PMID: 9568715, UI: 98227666

To: Peter Singleton who wrote (22190)	6/15/1998 7:52:00 AM
From: Henry Niman	Respond to of 32384

Here's another, including comments on atherosclerosis applications: Cell 1998 Apr 17;93(2):241-252 PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Tontonoz P, Nagy L, Alvarez JG, Thomazy VA, Evans RM The Salk Institute for Biological Studies, La Jolla, California 92037, USA. The formation of foam cells from macrophages in the arterial wall is characterized by dramatic changes in lipid metabolism, including increased expression of scavenger receptors and the uptake of oxidized low-density lipoprotein (oxLDL). We demonstrate here that the nuclear receptor PPARgamma is induced in human monocytes following exposure to oxLDL and is expressed at high levels in the foam cells of atherosclerotic lesions. Ligand activation of the PPARgamma:RXRalpha heterodimer in myelomonocytic cell lines induces changes characteristic of monocytic differentiation and promotes uptake of oxLDL through transcriptional induction of the scavenger receptor CD36. These results reveal a novel signaling pathway controlling differentiation and lipid metabolism in monocytic cells, and suggest that endogenous PPARgamma ligands may be important regulators of gene expression during atherogenesis.

To: Peter Singleton who wrote (22190)	6/15/1998 7:56:00 AM
From: Henry Niman	Respond to of 32384

Orphans also seem to be finding new ligands: Genes Dev 1998 May 1;12(9):1269-1277 BXR, an embryonic orphan nuclear receptor activated by a novel class of endogenous benzoate metabolites. Blumberg B, Kang H, Bolado J Jr, Chen H, Craig AG, Moreno TA, Umesono K, Perlmann T, De Robertis EM, Evans RM Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA. blumberg@axp1.salk.edu Nuclear receptors are ligand-modulated transcription factors that respond to steroids, retinoids, and thyroid hormones to control development and body physiology. Orphan nuclear receptors, which lack identified ligands, provide a unique, and largely untapped, resource to discover new principles of physiologic homeostasis. We describe the isolation and characterization of the vertebrate orphan receptor, BXR, which heterodimerizes with RXR and binds high-affinity DNA sites composed of a variant thyroid hormone response element. A bioactivity-guided screen of embryonic extracts revealed that BXR is activatable by low-molecular-weight molecules with spectral patterns distinct from known nuclear receptor ligands. Mass spectrometry and 1H NMR analysis identified alkyl esters of amino and hydroxy benzoic acids as potent, stereoselective activators. In vitro cofactor association studies, along with competable binding of radiolabeled compounds, establish these molecules as bona fide ligands. Benzoates comprise a new molecular class of nuclear receptor ligand and their activity suggests that BXR may control a previously unsuspected vertebrate signaling pathway. PMID: 9573044, UI: 98241485

To: Peter Singleton who wrote (22190)	6/15/1998 8:01:00 AM
From: Henry Niman	Respond to of 32384

In addition to synergizing with TZD's that activate PPARgamma, Targretin also synergizes with fibrates that activate PPARalpha (with applications to LOWER triglycerides): Arterioscler Thromb Vasc Biol 1998 Feb;18(2):272-276 RXR agonists activate PPARalpha-inducible genes, lower triglycerides, and raise HDL levels in vivo. Mukherjee R, Strasser J, Jow L, Hoener P, Paterniti JR Jr, Heyman RA Department of Pharmacology, Ligand Pharmaceuticals, Inc, San Diego, Calif. 92121, USA. mukherjee@ligand.com Peroxisome proliferator-activated receptors (PPARs) and retinoid X receptors (RXRs) are members of the intracellular receptor superfamily. PPARs bind to peroxisome proliferator-response elements (PPREs) as heterodimers with RXR and as such activate gene transcription in response to activators. Fibrates like gemfibrozil are well-known PPARalpha activators and are used in the treatment of hyperlipidemia. We show that the RXR ligand LGD1069 (Targretin), like gemfibrozil, can activate the PPARalpha/RXR signal-transduction pathway, including transactivation of the bifunctional enzyme or acyl-CoA oxidase response elements in a cotransfection assay. The activation also occurs in vivo, whereby in rats treated with LGD1069 or gemfibrozil, bifunctional enzyme and acyl-CoA oxidase RNA are induced and the combination of LGD1069 and gemfibrozil leads to a greater induction. Importantly, in hypertriglyceridemic db/db mice treated with RXR or PPARalpha agonists, triglyceride levels are lowered, and the combination again has significantly greater efficacy. RXR agonists also raise HDL cholesterol levels without changing apoA-I RNA expression. This observation suggests the use of RXR-selective agonists, "rexinoids," either alone or in combination with a fibrate as a new therapeutic approach to treating patients with high triglyceride and low HDL cholesterol levels. PMID: 9484993, UI: 98143524

To: Peter Singleton who wrote (22190)	6/15/1998 8:09:00 AM
From: Henry Niman	Read Replies (1) \| Respond to of 32384

It looks like the "phantom effect" of RXR ligands applies to PPARs also (an earlier publication indicated that such an effect could influence RARs): Mol Cell Biol 1998 Jun;18(6):3483-3494 Transactivation by retinoid X receptor-peroxisome proliferator-activated receptor gamma (PPARgamma) heterodimers: intermolecular synergy requires only the PPARgamma hormone-dependent activation function. Schulman IG, Shao G, Heyman RA Department of Retinoid Research, Ligand Pharmaceuticals, San Diego, California 92121, USA. [Medline record in process] The ability of DNA sequence-specific transcription factors to synergistically activate transcription is a common property of genes transcribed by RNA polymerase II. The present work characterizes a unique form of intermolecular transcriptional synergy between two members of the nuclear hormone receptor superfamily. Heterodimers formed between peroxisome proliferator-activated receptor gamma (PPARgamma), an adipocyte-enriched member of the superfamily required for adipogenesis, and retinoid X receptors (RXRs) can activate transcription in response to ligands specific for either subunit of the dimer. Simultaneous treatment with ligands specific for both PPARgamma and RXR has a synergistic effect on the transactivation of reporter genes and on adipocyte differentiation in cultured cells. Mutation of the PPARgamma hormone-dependent activation domain (named tauc or AF-2) inhibits the ability of RXR-PPARgamma heterodimers to respond to ligands specific for either subunit. In contrast, the ability of RXR- and PPARgamma-specific ligands to synergize does not require the hormone-dependent activation domain of RXR. The results of in vitro and in vivo experiments indicate that binding of ligands to RXR alters the conformation of the dimerization partner, PPARgamma, and modulates the activity of the heterodimer in a manner independent of the RXR hormone-dependent activation domain. PMID: 9584188, UI: 98252935