Identification of an N-oxide pyridine GW4064 analog as a potent FXR agonist

Feng, Song; Yang, Minmin; Zhang, Zhenshan; Wang, Zhanguo; Di, Hong J.; Richter, Hans G.; Benson, G. Martin; Bleicher, Konrad H.; Grether, Uwe; Martin, Rainer E.; Plancher, Jean‐Marc; Kuhn, Bernd; Rudolph, M.G.; Chen, Li

doi:10.1016/j.bmcl.2009.03.008

Cited by 48 publications

(37 citation statements)

References 23 publications

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“…In silico analysis of the binding mode of 4 in the FXR ligand binding site by molecular docking (PDB ID: https://www.rcsb.org/structure/3FXV, Figure a) suggested favorable occupation of the pocket defined by the co‐crystalized ligand. The chromenone carbonyl of 4 was placed close to the crystallized ligand's crucial acidic residue that forms key neutralizing contacts with Arg335.…”

Section: Resultsmentioning

confidence: 99%

“…Molecular modelling experiments were performed using MOE (Molecular Operating Environment v. 2016.08, Chemical Computing group, Montreal, Canada). Structure preparation of the FXR LBD (PDB ID: https://www.rcsb.org/structure/3FXV) was subjected to the Quick Preparation routine, which includes automated structure curation, determination of protonation state and restrained energy minimization. Afterward, molecular docking was performed using default settings for induced fit docking.…”

Section: Methodsmentioning

confidence: 99%

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Selective Optimization of Pranlukast to Farnesoid X Receptor Modulators

et al. 2018

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Selective optimization of side activities (SOSA) offers an alternative entry to early drug discovery and may provide rapid access to bioactive new chemical entities with desirable properties. SOSA aims to reverse a drug's side activities through structural modification and to design out the drug's original main action. We identified a moderate side activity for the cysteinyl leukotriene receptor 1 (CysLT1R) antagonist pranlukast on the farnesoid X receptor (FXR). Systematic structural modification of the drug allowed remarkable optimization of its partial FXR agonism to sub‐nanonmolar potency. The resulting FXR modulators lack any activity on CysLT1R and are characterized by high selectivity, high metabolic stability, and low toxicity. With their favorable in vitro profile, these SOSA‐derived FXR modulators constitute a new FXR ligand chemotype that appears suitable for further preclinical evaluation.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Selective Optimization of Pranlukast to Farnesoid X Receptor Modulators

et al. 2018

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“…39,95 Recently, a series of conforming constrained analogues of GW4064 have been synthesized, and their activities influence FXR. [96][97][98][99] Marine sponge steroids have also been recognized as novel nuclear receptor ligands. 70,100 Interestingly, some of them were discovered to be dual PXR and FXR ligands.…”

Section: Fxr Agonists For Treating Cholestatic Diseasesmentioning

confidence: 99%

Role of farnesoid X receptor in cholestasis

Yuan

2016

J of Digest Diseases

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The nuclear receptor farnesoid X receptor (FXR) plays an important role in physiological bile acid synthesis, secretion and transport. Defects of FXR regulation in these processes can cause cholestasis and subsequent pathological changes. FXR regulates the synthesis and uptake of bile acid via enzymes. It also increases bile acid solubility and elimination by promoting conjugation reactions and exports pump expression in cholestasis. The changes in bile acid transporters are involved in cholestasis, which can result from the mutations of transporter genes or acquired dysfunction of transport systems, such as inflammation-induced intrahepatic cholestasis. The modulation function of FXR in extrahepatic cholestasis is not identical to that in intrahepatic cholestasis, but the discrepancy may be reduced over time. In extrahepatic cholestasis, increasing biliary pressure can induce bile duct proliferation and bile infarcts, but the absence of FXR may ameliorate them. This review provides an update on the function of FXR in the regulation of bile acid metabolism, its role in the pathophysiological process of cholestasis and the therapeutic use of FXR agonists.

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“…For pharmacophore model generation, a systematic understanding of ligand binding and the elucidation of essential amino acids participating in the process is crucial. Therefore, the published X-ray crystal structures of FXR-ligand complexes available at the time of this study were extracted from the Protein Data Bank 34 (PDB, entries 1osh, 35 3bej, 36 3dct, 37 3dcu, 37 3fli, 38 3fxv, 39 3gd2, 40 3hc5, 41 and 3hc6; 41 Fig. 3) and analyzed for their protein–ligand interactions (Table 1).…”

Section: Resultsmentioning

confidence: 99%