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Design and synthesis of benzofused heterocyclic RXR modulators
D L Gernert1, D A Neel, M F Boehm
1Discovery Chemistry Research, Lilly Research Laboratories, Indianapolis, IN 46285, USA. dgernert@lilly.com
Bioorganic & Medicinal Chemistry Letters
|May 6, 2004
Summary
New benzofused heterocyclic compounds were synthesized and tested as selective modulators for Retinoid X Receptor (RXR). Their binding affinity and activation of RXR dimers depend on the specific heterocycle and sidechain used.
Area of Science:
- Medicinal Chemistry
- Molecular Pharmacology
- Drug Discovery
Background:
- Retinoid X Receptor (RXR) selective modulators are crucial therapeutic targets.
- LG101506 is a known RXR selective modulator.
- Benzofused heterocycles represent a novel structural class for modulating RXR activity.
Purpose of the Study:
- To synthesize novel benzofused heterocyclic analogs of LG101506.
- To evaluate the binding affinity of these analogs to RXRalpha.
- To assess their ability to activate RXR homo and heterodimers.
Main Methods:
- Chemical synthesis of benzofused heterocyclic compounds.
- In vitro assays to measure RXRalpha binding.
- Functional assays to determine RXR homo and heterodimer activation.
Main Results:
- Successful synthesis of diverse benzofused heterocyclic analogs.
- Demonstrated binding of synthesized compounds to RXRalpha.
- Observed that potency and efficacy are influenced by the heterocycle and sidechain structure.
Conclusions:
- Benzofused heterocycles are a promising scaffold for developing novel RXR modulators.
- Structural modifications, specifically the choice of heterocycle and sidechain, significantly impact RXR modulation.
- These findings provide a basis for further optimization of RXR-targeted therapeutics.