Recent advances in the design of RAR α and RAR β agonists as orally bioavailable drugs. A review

Borthwick, Alan D.; Goncalves, Maria B.; Corcoran, Jonathan

doi:10.1016/j.bmc.2020.115664

Cited by 16 publications

(10 citation statements)

References 44 publications

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“…Given the unmet demand for anti‐ALD drugs 69 and growing evidence of the therapeutic potential of newer generation RAR‐specific agonists, 70 our data support a novel approach for prevention of ALD progression with synthetic agonists for RARβ2 23 …”

Section: Discussionmentioning

confidence: 78%

A retinoic acid receptor β2 agonist protects against alcohol liver disease and modulates hepatic expression of canonical retinoid metabolism genes

et al. 2021

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Alcohol abuse reduces hepatic vitamin A (retinoids), reductions that are associated with progression of alcohol liver disease (ALD). Restoring hepatic retinoids through diet is contraindicated in ALD due to the negative effects of alcohol on retinoid metabolism. There are currently no drugs that can both mitigate alcoholdriven hepatic retinoid losses and progression of ALD. Using a mouse model of alcohol intake, we examined if an agonist for the retinoic acid (RA) receptor β2 (RARβ2), AC261066 (AC261) could prevent alcohol-driven hepatic retinoid losses and protect against ALD. Our results show that mice co-treated with AC261 and alcohol displayed mitigation of ALD, including reduced macro, and microvesicular steatosis, and liver damage. Alcohol intake led to increases in hepatic centrilobular levels of ALDH1A1, a rate-limiting enzyme in RA synthesis, and colocalization of ALDH1A1 with the alcohol-metabolizing enzyme CYP2E1, and 4-HNE, a marker of oxidative stress; expression of these targets was abrogated in mice co-treated with AC261 and alcohol. By RNA sequencing technology, we found that AC261 treatments opposed alcohol modulation of 68 transcripts involved in canonical retinoid metabolism. Alcohol modulation of these transcripts, including CES1D, CES1G, RBP1, RDH10, and CYP26A1, collectively favor hepatic retinoid hydrolysis and catabolism. However, despite this, coadministration of AC261 with alcohol did not mitigate alcohol-mediated depletions of hepatic retinoids, but did reduce alcohol-driven increases in serum retinol.

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Section: Discussionmentioning

confidence: 78%

A retinoic acid receptor β2 agonist protects against alcohol liver disease and modulates hepatic expression of canonical retinoid metabolism genes

et al. 2021

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“…This RARγ-selective activity profile is quite different from the RARαselective profile of benzanilide-type retinoids such as Am80 (3) and 4. Though clinical applications of RARγ ligands have been less well investigated compared to those of RARα and RARβ ligands, [30] RARγ ligands do have therapeutic potential. [31][32][33][34][35] Compound 24 c might be a promising lead compound for RARγ-selective ligands.…”

Section: Discussionmentioning

confidence: 99%

Structural Development of Silicon‐Containing Retinoids: Structure–Activity Relationship Study of the Hydrophobic Pharmacophore of Retinobenzoic Acids Using Silyl Functionalities

et al. 2022

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We designed and synthesized a series of retinobenzoic acids bearing various silyl functionalities in order to explore in detail the structure‐activity relationship (SAR) at the hydrophobic moiety of retinoids. Among the synthesized compounds, 24 c bearing a t‐butyldimethylsilyl (TBS) group at the hydrophobic site exhibited potent retinoid activity comparable to that of the lead compound Am555S (4). Compound 24 c exhibited transcription‐promoting activity towards all three subtypes of retinoic acid receptor (RAR), but showed the highest activity towards RARγ, in contrast to the high RARα‐selectivity of Am80 (3) and Am555S (4). The SARs presented here should be helpful in the development of subtype‐selective retinoids, and in particular 24 c might be a promising lead compound for new RARγ ligands.

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“…69,70 Moreover, it has been shown that binding of drugs to this transcription factors can impact its activity and consequently modulate cell functions. 71 Similarly, several studies also identified several molecules presenting high affinity for HNF4α affecting its activity. 72 Therefore, it could be suggested that epicatechin metabolites by interacting with these proteins will modulate their activities, resulting in changes in the expression of identified genes and exert their health properties.…”

Section: Papermentioning

confidence: 96%

(−)-Epicatechin exerts positive effects on anxiety in high fat diet-induced obese mice through multi-genomic modifications in the hippocampus

2022

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Recent advances in the design of RAR α and RAR β agonists as orally bioavailable drugs. A review

Abstract: Graphical abstract

Cited by 16 publications

References 44 publications

A retinoic acid receptor β2 agonist protects against alcohol liver disease and modulates hepatic expression of canonical retinoid metabolism genes

A retinoic acid receptor β2 agonist protects against alcohol liver disease and modulates hepatic expression of canonical retinoid metabolism genes

Structural Development of Silicon‐Containing Retinoids: Structure–Activity Relationship Study of the Hydrophobic Pharmacophore of Retinobenzoic Acids Using Silyl Functionalities

(−)-Epicatechin exerts positive effects on anxiety in high fat diet-induced obese mice through multi-genomic modifications in the hippocampus

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