Structure-based design of potent retinoid X receptor alpha agonists.
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Haffner CD, Lenhard JM, Miller AB, McDougald DL, Dwornik K, Ittoop OR, Gampe RT Jr, Xu HE, Blanchard S, Montana VG, Consler TG, Bledsoe RK, Ayscue A, Croom D
Structure-based design of potent retinoid X receptor alpha agonists.
J Med Chem. 2004 Apr 8;47(8):2010-29.
- PubMed ID
- 15056000 [ View in PubMed]
- Abstract
A series of tetrahydrobenzofuranyl and tetrahydrobenzothienyl propenoic acids that showed potent agonist activity against RXRalpha were synthesized via a structure-based design approach. Among the compounds studied, 46a,b showed not only very good potency against RXRalpha (K(i) = 6 nM) but was also found to be greater than 167-fold selective vs RARalpha (K(i) > 1000 nM). This compound profiled out as a full agonist in a cell-based transient transfection assay (EC(50) = 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 RXRalpha 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.