DrugBank screening revealed alitretinoin and bexarotene as liver X receptor modulators

Selective Optimization of Pranlukast to Farnesoid X Receptor Modulators

“…Pranlukast descendants 5-25 were synthesized accordingt o Scheme2-Scheme 7. Carboxylic acidb uilding blocks 26-30 serveda sp recursors fora ll synthesis routeso fw hich [26][27][28][29] were prepared in at wo-step procedure using methyl 4-hydroxybenzoate (31)o rm ethyl3 -hydroxybenzoate (32)f or William-Selectiveo ptimization of side activities (SOSA) offers an alternative entry to early drug discoverya nd may provide rapid access to bioactive new chemical entitiesw ith desirable properties. SOSA aims to reverse ad rug'ss ide activities through structural modification and to design out the drug'so riginal main action.…”

“…Hybrid reporter gene assays for PPARa/g/d,L XRa/b,R XRa, RARa,VDR, CAR and PXR. Plasmids:T he Gal4-fusion receptor plasmids pFA-CMV-hPPARa-LBD, [25] pFA-CMV-hPPARgLBD, [25] pFA-CMV-hPPARd-LBD, [25] pFA-CMV-hLXRa-LBD, [26] pFACMV-hLXRb-LBD, [26] pFA-CMV-hRXRa-LBD, [27] pFA-CMV-hRARa-LBD, [27] pFA-CMV-hVDR-LBD, [27] pFA-CMV-hCAR-LBD, [27] and pFA-CMV-hPXR-LBD [27] coding for the hinge region and ligand binding domain (LBD) of the canonical isoform of the respective nuclear receptor have been reported previously.p FR-Luc (Stratagene) was used as reporter plasmid and pRL-SV40 (Promega) for normalization of transfection efficiency and cell growth. Assay procedure:H EK293T cells were grown in DMEM high glucose, supplemented with 10 %F CS, sodium pyruvate (1 mm), penicillin (100 UmL À1 ), and streptomycin (100 mgmL À1 )a t3 7 8Ca nd 5% CO 2 .T he day before transfection, HEK293T cells were seeded in 96-well plates (2.5 10 4 cells per well).…”

“…Phenylbutoxy)benzoic acid(26): Preparation according to general procedure Au sing methyl 4-(4-phenylbutoxy)benzoate (36, 0.56 g, 2.0 mmol, 1.0 equiv), LiOH (0.08 g, 4.0 mmol, 2.0 equiv) to yield 26 as ac olorless solid. 26 was used without further purification (0.37 g, 68 %).1 HNMR (250 MHz, [D 6 ]DMSO): d = 12.55 (s, 1H), 7.86 (d, J = 8.9 Hz, 2H), 7.32-7.13 (m, 5H), 6.99 (d, J = 8.9 Hz, 2H), 4.06 (t, J = 5.9 Hz, 2H), 2.64 (t, J = 7.0 Hz, 2H), 1.79-1.67 ppm (m, 4H); 13 CNMR (126 MHz, [D 6 ]DMSO): d = 167.01;1 62.27;1 41.97; 131.34;1 28.32;1 28.29;1 25.74;1 22.81;1 14.23;6 7.61;3 4.73;2 8.11; 27.36 ppm;M S(ESIÀ): m/z 269.13 ([MÀH] À ).3-(4-Phenylbutoxy)benzoic acid (27): Preparation according to general procedure Au sing methyl 3-(4-phenylbutoxy)benzoate (37, 0.65 g, 2.3 mmol, 1.0 equiv), LiOH (0.11g,4 .6 mmol, 2.0 equiv) to yield 27 as ac olorless solid.…”

Allosteric modulation of the farnesoid X receptor by a small molecule

“…Since 4 significantly increased the transactivation efficacy of orthosteric FXR agonists 1 – 3 , partial agonistic FXR modulation by 4 is not a result of orthosteric binding. In presence of an orthosteric full agonist, an orthosteric partial agonist would displace the agonists from the binding site and behave as partial antagonist 26 . Involvement of FXR’s heterodimer partner RXR in FXR modulation by 4 can be excluded since no agonistic or antagonistic activity of 4 on a specific Gal4-DBD-RXR-LBD hybrid receptor was observed.…”

Urate transporter inhibitor lesinurad is a selective peroxisome proliferator-activated receptor gamma modulator (sPPARγM) in vitro

“…The Gal4-fusion receptor plasmids pFA-CMV-hPPARα-LBD 50 , pFA-CMV-hPPARγ-LBD 50 , pFA-CMV-hPPARδ-LBD 50 , pFA-CMV-hLXRα-LBD 51 , pFA-CMV-hLXRβ-LBD 51 , pFA-CMV-hRXRα-LBD 52 , pFA-CMV-hRXRβ-LBD 52 , pFA-CMV-hRXRγ-LBD 52 , pFA-CMV-hRARα-LBD 52 , pFA-CMV-hRARβ-LBD 52 , pFA-CMV-hRARγ-LBD 52 , pFA-CMV-hFXR-LBD 53 , pFA-CMV-hVDR-LBD 52 , pFA-CMV-hCAR-LBD 52 and pFA-CMV-hPXR-LBD 52 coding for the hinge region and ligand binding domain (LBD) of the canonical isoform of the respective nuclear receptor have been reported previously. pFR-Luc (Stratagene) was used as reporter plasmid and pRL-SV40 (Promega) for normalization of transfection efficiency and cell growth.…”