- Antidiabetic actions of a non-agonist PPARγ ligand blocking Cdk5-mediated phosphorylation
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PPARγ is the functioning receptor for the thiazolidinedione (TZD) class of antidiabetes drugs including rosiglitazone and pioglitazone. These drugs are full classical agonists for this nuclear receptor, but recent data have shown that many PPARγ-based drugs have a separate biochemical activity, blocking the obesity-linked phosphorylation of PPARγ by Cdk5 (ref. 2). Here we describe novel synthetic compounds that have a unique mode of binding to PPARγ, completely lack classical transcriptional agonism and block the Cdk5-mediated phosphorylation in cultured adipocytes and in insulin-resistant mice. Moreover, one such compound, SR1664, has potent antidiabetic activity while not causing the fluid retention and weight gain that are serious side effects of many of the PPARγ drugs. Unlike TZDs, SR1664 also does not interfere with bone formation in culture. These data illustrate that new classes of antidiabetes drugs can be developed by specifically targeting the Cdk5-mediated phosphorylation of PPARγ. 2011 Macmillan Publishers Limited. All rights reserved.
- Choi, Jang Hyun,Banks, Alexander S.,Kamenecka, Theodore M.,Busby, Scott A.,Chalmers, Michael J.,Kumar, Naresh,Kuruvilla, Dana S.,Shin, Youseung,He, Yuanjun,Bruning, John B.,Marciano, David P.,Cameron, Michael D.,Laznik, Dina,Jurczak, Michael J.,Schuerer, Stephan C.,Vidovic, Dusica,Shulman, Gerald I.,Spiegelman, Bruce M.,Griffin, Patrick R.
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- PPARG MODULATORS FOR TREATMENT OF OSTEOPOROSIS
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The invention provides methods of treatment of a progressive bone disease, such as osteoporosis, Paget's Disease, multiple myeloma, or hyperparathyroidism, comprising administration of an effective amount of a non-agonist PPARG modulator to a patient afflicted with the disease.
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- N-BIPHENYLMETHYLINDOLE MODULATORS OF PPARG
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The invention provides molecular entities that bind with high affinity to PPARG (PPAR3), inhibit kinase-mediated, e.g., cdk5-mediated, phosphorylation of PPARG, but do not exert an agonistic effect on PPARG. Compounds of the invention can be used for treatment of conditions in patients wherein PPARG plays a role, such as diabetes, insulin resistance, impaired glucose tolerance, pre-diabetes, hyperglycemia, hyperinsulinemia, obesity, or inflammation. In methods of treatment of these conditions using a compound of the invention, the compound can avoid producing side effects of significant weight gain, edema, impairment of bone growth or formation, or cardiac hypertrophy, or any combination thereof, in the patient receiving the compound. Methods of preparation of the compounds, bioassay methods for evaluating compounds of the invention as non-agonistic PPARG binding compounds, and pharmaceutical compositions are also provided.
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- Synthesis and biological activities of novel indole derivatives as potent and selective PPARγ modulators
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Starting from the structure of Telmisartan, a new series of potent and selective PPARγ modulators was identified. The synthesis, in vitro and in vivo evaluation of the most potent compounds are reported and the X-ray structure of compound 7b bound to the PPARγ ligand binding domain is described.
- Lamotte, Yann,Martres, Paul,Faucher, Nicolas,Laroze, Alain,Grillot, Didier,Ancellin, Nicolas,Saintillan, Yannick,Beneton, Véronique,Gampe Jr., Robert T.
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supporting information; experimental part
p. 1399 - 1404
(2010/07/06)
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