Nonacidic Farnesoid X Receptor Modulators

Abstract

As a cellular bile acid sensor, farnesoid X receptor (FXR) participates in regulation of bile acid, lipid and glucose homeostasis, and liver protection. Clinical results have validated FXR as therapeutic target in hepatic and metabolic diseases. To date, potent FXR agonists share a negatively ionizable function that might compromise their pharmacokinetic distribution and behavior. Here we report the development and characterization of a high-affinity FXR modulator not comprising an acidic residue.

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).…”

Tuning artificial intelligence on the de novo design of natural-product-inspired retinoid X receptor modulators

“…These in vitro test systems employ chimera receptors composed of the human ligand binding domain of the nuclear receptor in question and the DNA binding domain of the Gal4 receptor from yeast. A Gal4-responsive firefly luciferase construct served as reporter gene and a constitutively expressed Renilla luciferase was used to normalize on transfection efficiency and observe test compound toxicity 25,26 . Designs 7-10 were tested for both agonistic and competitive antagonistic activity.…”

“…Benchmark fingerprints were computed with the "RDKit Fingeprints" node in KNIME 35 Hybrid reporter gene assays for RXRα/β/γ activation. Gal4 hybrid reporter gene assays were performed as described previously 25,26 . Plasmids: The Gal4-fusion receptor plasmids pFA-CMV-hRXRα-LBD 26 , pFA-CMV-hRXRβ-LBD 26 , and pFA-CMV-hRXRγ-LBD 26 coding for the hinge region and ligand binding domain (LBD) of the canonical isoform of the respective nuclear receptor have been reported previously.…”

Computer‐Assisted Selective Optimization of Side‐Activities—from Cinalukast to a PPARα Modulator

“…PPARa modulatory activity of 1 and derivatives 2-4 wasd etermined in as pecific PPARa-Gal4 hybrid reporterg ene assay [9,10] relying on ac himericr eceptor composed of the human PPARa ligand binding domain (LBD) and the DNA binding domain of the receptor Gal4 from yeast to govern reporter gene expression. AGal4-inducible firefly luciferase served as reporter,and a constitutively expressed Renilla luciferase was used to monitor test compound toxicitya nd transfection efficiency.C ysLT 1 Ra ntagonism of 1 and 4 was assessed in ac ell-based Ca 2 + -flux assay in competition with 0.1 nm leukotriene D4.…”