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Recent advances in the design of RAR α and RAR β agonists as orally bioavailable drugs. A review
Alan D Borthwick1, Maria B Goncalves2, Jonathan P T Corcoran2
1DrugMolDesign, 15 Temple Grove, London NW11 7UA, UK.
Abstract:
Retinoic acid receptors (RARs) α, β, and γ are members of the nuclear receptor superfamily. Compounds which bind to and activate the RARs are termed retinoids which regulate a wide variety of biological processes such as vertebrate embryonic morphogenesis and organogenesis, cell growth arrest, differentiation, and apoptosis, as well as their disorders. Although many synthetic selective RARα, RARβ, and RARγ agonists have been designed and prepared, these have generally been lipophilic acids without good drug-like properties and with low oral bioavailability. Recently this has been changing and drug design approaches to highly potent and selective RARα and RARβ agonists with low lipophilicity that are orally bioavailable and less toxic have been developed, that have a range of potential therapeutic uses. This review covers these new advances.
Insights
New drug design approaches yield orally bioavailable retinoids that target retinoic acid receptors (RARs) α and β. These potent and selective agonists offer improved drug-like properties and reduced toxicity for potential therapeutic applications.
Area of Science:
- Molecular Biology
- Pharmacology
- Drug Discovery
Background:
- Retinoic acid receptors (RARs) α, β, and γ are nuclear receptors regulating critical biological processes.
- Retinoids, compounds activating RARs, are involved in development, cell growth, differentiation, and apoptosis.
- Traditional synthetic RAR agonists often exhibit poor drug-like properties and low oral bioavailability.
Purpose of the Study:
- To review recent advances in the design of novel retinoic acid receptor agonists.
- To highlight the development of orally bioavailable and selective RARα and RARβ agonists.
- To discuss the therapeutic potential of these new drug candidates.
Main Methods:
- Review of recent literature on synthetic retinoid drug design.
- Analysis of structure-activity relationships for selective RAR agonists.
- Evaluation of pharmacokinetic and toxicological profiles of novel compounds.
Main Results:
- Development of highly potent and selective RARα and RARβ agonists.
- Achieved low lipophilicity and improved oral bioavailability in new retinoid designs.
- Demonstrated reduced toxicity compared to previous generations of RAR agonists.
Conclusions:
- Recent drug design strategies have successfully overcome limitations of earlier retinoids.
- New selective RARα and RARβ agonists possess favorable drug-like properties and therapeutic potential.
- These advancements pave the way for new treatments targeting RAR-mediated pathways.
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