Details

Autor(en) / Beteiligte

• Haffner, Curt D.
• Lenhard, James M.
• Miller, Aaron B.
• McDougald, Darryl L.
• Dwornik, Kate
• Ittoop, Olivia R.
• Gampe, Robert T.
• Xu, H. Eric
• Blanchard, Steve
• Montana, Valerie G.
• Consler, Tom G.
• Bledsoe, Randy K.
• Ayscue, Andrea
• Croom, Dallas

Titel

Structure-Based Design of Potent Retinoid X Receptor α Agonists

Ist Teil von

• Journal of medicinal chemistry, 2004-04, Vol.47 (8), p.2010-2029

Ort / Verlag

Washington, DC: American Chemical Society

Erscheinungsjahr

2004

Quelle

MEDLINE

Beschreibungen/Notizen

• A series of tetrahydrobenzofuranyl and tetrahydrobenzothienyl propenoic acids that showed potent agonist activity against RXRα were synthesized via a structure-based design approach. Among the compounds studied, 46a,b showed not only very good potency against RXRα (K i = 6 nM) but was also found to be greater than 167-fold selective vs RARα (K i > 1000 nM). This compound profiled out as a full agonist in a cell-based transient transfection assay (EC50 = 3 nM). The two antipodes were separated via chiral chromatography, and 46b was found to be 40-fold more potent than 46a. Interestingly, cocrystallization of 46a,b with the RXRα protein generated a liganded structure whereby the (S)-antipode was found in the binding pocket. Given orally in db/db mice or ZDF rats, 46a,b showed a significant glucose-lowering effect and an increase in liver mass. Triglycerides decreased significantly in db/db mice but increased in the ZDF rats. A dose-dependent decrease of nonesterified free fatty acids was seen in ZDF rats but not in db/db mice. These differences indicate a species specific effect of RXR agonists on lipid metabolism.