516518-24-4Relevant academic research and scientific papers
Large Dimeric Ligands with Favorable Pharmacokinetic Properties and Peroxisome Proliferator-Activated Receptor Agonist Activity in Vitro and in Vivo
Sauerberg, Per,Bury, Paul S.,Mogensen, John P.,Deussen, Heinz-Josef,Pettersson, Ingrid,Fleckner, Jan,Nehlin, Jan,Frederiksen, Klaus S.,Albrektsen, Tatjana,Din, Nanni,Svensson, L. Anders,Ynddal, Lars,Wulff, Erik M.,Jeppesen, Lone
, p. 4883 - 4894 (2007/10/03)
Two potent nonselective, but PPARα-preferring, PPAR agonists 5 and 6 were designed and synthesized in high yields. The concept of dimeric ligands in transcription factors was investigated by synthesizing and testing the corresponding dimers 7, 8a, and 8b in PPAR transactivation assays. The three dimeric ligands all showed agonist activity on all three PPAR receptor subtypes, but with different profiles compared to the monomers 5 and 6. Despite breaking all the "rule of five" criteria, the dimers had excellent oral bioavailability and pharmacokinetic properties, resulting in good in vivo efficacy in db/db mice. X-ray crystal structure and modeling experiments suggested that the dimers interacted with the AF-2 helix as well as with amino acid residues in the lipophilic pocket close to the receptor surface.
Novel compounds, their preparation and use
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, (2008/06/13)
A novel class of dicarboxylic acid derivatives, the use of these compounds as pharmaceutical compositions, pharmaceutical compositions comprising the compounds and methods of treatment employing these compounds and compositions. The present compounds may be useful in the treatment and/or prevention of conditions mediated by Peroxisome Proliferator-Activated Receptors (PPAR).
