- Novel tricyclic-α-alkyloxyphenylpropionic acids: Dual PPARα/γ agonists with hypolipidemic and antidiabetic activity
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Synthesis and structure-activity relationships of tricyclic α-ethoxy-phenylpropionic acid derivatives guided by in vitro PPARα and PPARγ transactivation data and computer modeling led to the identification of the novel carbazole analogue, 3q, with and dual PPARα (EC50 = 00.36 μM) and PPARγ (EC50 = 0.17 μM) activity in vitro. Ten days treatment of db/db mice with 3q improved the insulin sensitivity, as measured by OGTT, better than that seen with both pioglitazone and rosiglitazone treatment, suggesting in vivo PPARγ activity. Likewise, 3q lowered plasma triglycerides and cholesterol in high cholesterol fed rats after 4 days treatment, indicating in vivo PPARα activity. Investigations of the pharmacokinetics of selected compounds suggested that extended drug exposure improved the in vivo activity of in vitro active compounds.
- Sauerberg, Per,Pettersson, Ingrid,Jeppesen, Lone,Bury, Paul S.,Mogensen, John P.,Wassermann, Karsten,Brand, Christian L.,Sturis, Jeppe,W?ldike, Helle F.,Fleckner, Jan,Andersen, Anne-Sofie T.,Mortensen, Steen B.,Svensson, L. Anders,Rasmussen, Hanne B.,Lehmann, S?ren V.,Polivka, Zdenek,Sindelar, Karel,Panajotova, Vladimira,Ynddal, Lars,Wulff, Erik M.
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p. 789 - 804
(2007/10/03)
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- Compounds, their preparation and use
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The present invention relates to compounds of the general formula (I) The compounds are useful in the treatment and/or prevention of conditions mediated by nuclear receptors, in particular the Peroxisome Proliferator-Activated Receptors (PPAR).
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Page column 33
(2010/11/29)
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