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The farnesoid X receptor (FXR) is a nuclear receptor that acts as a master regulator of bile acid metabolism and signaling. Activation of FXR inhibits bile acid synthesis and increases bile acid conjugation, transport, and excretion, thereby protecting the liver from the harmful effects of bile accumulation, leading to considerable interest in FXR as a therapeutic target for the treatment of cholestasis and nonalcoholic steatohepatitis. We identified a novel series of highly potent non-bile acid FXR agonists that introduce a bicyclic nortropine-substituted benzothiazole carboxylic acid moiety onto a trisubstituted isoxazole scaffold. Herein, we report the discovery of 1 (tropifexor, LJN452), a novel and highly potent agonist of FXR. Potent in vivo activity was demonstrated in rodent PD models by measuring the induction of FXR target genes in various tissues. Tropifexor has advanced into phase 2 human clinical trials in patients with NASH and PBC.

The structure and activity of the pseudodisaccharide core found in aminoglycoside antibiotics was probed with a series of synthetic analogues in which the position of amino groups was varied around the glucopyranose ring. The naturally occurring structure neamine was the best in the series according to assays for in vitro RNA binding and antibiotic activity. With this result in hand, neamine was used as a common core structure for the synthesis of new antibiotics, which were evaluated for binding to models of the Escherichia coli 16S A-site ribosomal RNA, in vitro protein synthesis inhibition, and antibiotic activity. Analysis of RNA binding revealed some correlation between the relative affinity and specificity of RNA binding and antibacterial efficacy. However, the correlation was not linear. This result led us to develop the in vitro translation assay in an effort to better understand aminoglycoside−RNA interactions. A linear correlation between in vitro translation inhibition and antibiotic activity was observed. In addition, IC50s in the protein synthesis assay were typically lower than the K ds obtained for RNA binding, suggesting that binding of these compounds to intact ribosomes is tighter in these cases than binding to the model RNA oligonucleotides. This reflects possible differences in RNA conformation between intact ribosomes and the free RNA of the model system, or possible high-affinity ribosomal binding sites in addition to the A-site RNA.

The binding of neomycin B and related aminoglycoside antibiotics to the prokaryotic ribosomal RNA decoding region has been investigated using a recently developed surface plasmon resonance assay. A number of naturally occurring aminoglycosides containing a neamine or neamine-like substructure bind specifically to a model of the site of the ribosomal decoding region RNA. This recognition event is the basis of the antibacterial activity of this class of compounds. A series of analogs was designed and synthesized to probe the role of neomycin ring IV (2,6-dideoxy-2,6-diamino-β-l-idopyranose). The binding results indicate that the positive charge presented on the idose ring is necessary for specific binding in vitro and cannot be replaced by amines attached via flexible linkers. However, the antibiotic activity (minimum inhibitory concentration) of the analog where ring IV is replaced with a diamine tail is the same as neomycin B in a liquid culture assay against Escherichia coli.

The role of the bifunctional catalyst is decisive: The magnesium ion as Lewis acid and its nucleophilic iodide counterion contribute in synergy to the successful ring expansion of the cyclopropane 1 by aldimine 2 [Eq. (1)]. This reaction offers a novel route to spiro[pyrrolidin‐3,3′‐oxindoles] 3.

The 11S proteasome activators are shown to be important for both increasing the activity of the 20S proteasome and for altering its cleavage pattern and substrate specificity. These data also establish that the extended substrate specificity is an important factor for proteasomal cleavage. The specificities observed have features in common with major histocompatibility complex (MHC) class I ligands and can be used to improve the prediction of MHC class I restricted cytotoxic T-cell responses.

Et THFlNMP Ph-CZC-Et t -35 'C, 3 h 13 : 88 %; Z : € 9 9 : 1 2) 12 0c IPd(dba)n] (4 rnol%) Ph,P (16 rnol%) THF. 55 'C, 10 h. then HCI n HN+Me2 C I -14 : (Z)-tamoxiten 75%;Z: € > 9 9 : 1Scheme 4. Synthesis of (2)-tamoxifen (14).In summary, we have reported a new intramolecular syn carbonickelation leading to alkylated exo-alkylidenecyclopentane derivatives, as well as an intermolecular carbozincation of substituted phenylacetylenes that allows stereoselective (> 98 % syn addition) synthesis of tri-and tetrasubstituted phenylalkenes. Experimental Procedures(12b): [Ni(acac),] (320 mg, 1.25 mmol, 25 mol%) and 8d (0.89 g, 5 mmol, 1 equiv) were dissolved in T H F (3 75mL) and NMP (1.25mL) at -4O'C under argon. Diethylzinc ( I .O mL. 10 mmol, 2 equiv) was carefully added via syringe at -78 "C. The reaction mixture was allowed to warm to -35'C and stirred for 2.5 h. Meanwhile a mixture of CuCN (1 79 g, 20 mmol, 4 equiv) and LiCl (1 69 g, 40 mmol, 8 equiv) was dried in VaCUO at 130 "C for 2 h and then dissolved in T H F (10 mL). The solution was cooled to -60°C and added by syringe to the reaction mixture at -78 C. The resulting dark solution was warmed to 0°C for a few minutes and then again cooled to -78'C. Ethyl (a-brom~methyl)acrylate'~' (4.82 g, 25 mmol, 5 equiv) was added, and the reaction mixture warmed to 25°C and worked up. The crude product was purified by flash-chromatography (hexanesiether 20/1), affording the ester 12b (1.13 g, 3.53 mmol, 71 % yield; Z:E>99:1) as a white powder. (5c): [Ni(acac)J (96 mg. 0.37 mmol, 7 mol%) was dissolved in T H F (3.75 mL) and NMP (1 2 5 mL) at -40 'C under argon, and 1 -iodo-4-phenyl-5-hexyne (4b) (I .41 g, 5 mmol, 1 equiv) was added At z 7 8 " C , Pent& (2.0 mL, 10 mmol, 2 equiv) was carefully added by syringe. The reaction mixture was stirred for 30 h at -40°C. After the usual workup. the solvents were distilled off, and the crude residue was purified by chromatography (hexanes) to give the cyclized product 5c (0.74g 3.24mmol. 65% yield: E:Z>99:1) as a colorless oil.

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