Farnesoid X-activated receptor antagonists from a marine sponge Spongia sp.

Nam, Sang Jip; Ko, Hyunsil; Shin, Min Kyoung; Ham, Jungyeob; Chin, Jungwook; Kim, Young-Shin; Kim, Heeyoung; Shin, Kyoungjin; Choi, Hyukjae; Kang, Heonjoong

doi:10.1016/j.bmcl.2006.07.079

Cited by 46 publications

(27 citation statements)

References 20 publications

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“…17 In addition, several scalarane sesterterpenes, isolated from a marine sponge, inhibited FXR with IC 50 values between 2.4 and 24 µM. 18 Most recently, suvanine, a marine sponge sesterterpene, was reported by Di Leva et al as an FXR antagonist. 19 Using suvanine as a template, Di Leva et al developed suvanine derivative as a novel FXR antagonist (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Identification of trisubstituted-pyrazol carboxamide analogs as novel and potent antagonists of farnesoid X receptor

Lin

Forman

et al. 2014

Bioorganic & Medicinal Chemistry

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Farnesoid X receptor (FXR, NRIH4) plays a major role in the control of cholesterol metabolism. This suggests that antagonizing the transcriptional activity of FXR is a potential means to treat cholestasis and related metabolic disorders. Here we describe the synthesis, biological evaluation, and structure-activity relationship (SAR) studies of trisubstituted-pyrazol carboxamides as novel and potent FXR antagonists. One of these novel FXR antagonists, 4j has an IC50 of 7.5 nM in an FXR binding assay and 468.5 nM in a cell-based FXR antagonistic assay. Compound 4j has no detectable FXR agonistic activity or cytotoxicity. Notably, 4j is the most potent FXR antagonist identified to date; it has a promising in vitro profile and could serve as an excellent chemical tool to elucidate the biological function of FXR.

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Section: Introductionmentioning

confidence: 99%

Identification of trisubstituted-pyrazol carboxamide analogs as novel and potent antagonists of farnesoid X receptor

Lin

Forman

et al. 2014

Bioorganic & Medicinal Chemistry

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“…(5)) and 12-Odeacetyl-12-epi-19-deoxy-21-hydroxyscalarin (8 in Fig. (5)) the most potent of this series, showing IC 50 values of 8.1 μM and 2.4 μM, respectively [230,231]. Moreover, the loss of activity in derivatives 2-7 and 9 Fig.…”

Section: Several Phenolic Derivative Have Been Described As Fxr Agonimentioning

confidence: 91%

Natural Ligands for Nuclear Receptors: Biology and Potential Therapeutic Applications

D’Auria¹,

Sepe²,

Zampella

2012

CTMC

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Nuclear receptors are key regulators of various processes including reproduction, development, and metabolism of xeno- and endobiotics. Research in the last two decades has focused to the development of novel drugs specifically targeting nuclear receptors for the treatment of a variety of diseases, such as cancer, diabetes, dyslipidemia, fatty liver disease, drug hepatotoxicity and cholestasis. The search for novel NRs agonists and antagonists with enhanced selectivity prompted the exploration of the extraordinary chemical diversity associated to natural products. In recent years a number of natural products were disclosed as ligands of NRs and proved to have remarkable affinity and in some cases peculiar mode of action. In this review the natural ligands of the subfamily NR1, NR2, and NR3 will be described with an emphasis to their mechanisms of action and pharmacological profiles.

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“…In contrast to FXR agonists, only a small number of FXR antagonists are identified. These include guggulsterone [27], Stigmasterol [28] and scalarane sesterterpenes [29,30].…”

Section: Fxr Ligandsmentioning

confidence: 99%

Fxr

Wang¹,

Chen²,

Chen³

et al. 2010

Nuclear Receptors

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Abstract:Great progress has been made in the understanding of the physiological roles of the nuclear receptor farnesoid X receptor (FXR) during the last several years. Roles for FXR were initially identified in the regulation of bile acid, cholesterol, triglyceride, and glucose metabolism. More recently, additional functions of FXR are identified in enteroprotection, liver regeneration, cancer and aging. These exciting findings suggest that FXR has a broader role than previously thought, and also highlight potential opportunities for using FXR as a drug target for different diseases. 12

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Farnesoid X-activated receptor antagonists from a marine sponge Spongia sp.

Cited by 46 publications

References 20 publications

Identification of trisubstituted-pyrazol carboxamide analogs as novel and potent antagonists of farnesoid X receptor

Identification of trisubstituted-pyrazol carboxamide analogs as novel and potent antagonists of farnesoid X receptor

Natural Ligands for Nuclear Receptors: Biology and Potential Therapeutic Applications

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