Pyrazine arotinoids with inverse agonist activities on the retinoid and rexinoid receptors. - Archive ouverte HAL Access content directly
Journal Articles ChemBioChem Year : 2009

Pyrazine arotinoids with inverse agonist activities on the retinoid and rexinoid receptors.

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Abstract

RAR and RXR agonists: A collection of pyrazine-based RAR/RXR ligands were prepared by a series of palladium catalyzed cross-coupling reactions and characterized. Structure-activity relationships were elucidated. Retinoic acid receptor (RAR) alpha/beta-subtype-selective and retinoid X receptor (RXR) inverse agonist activities are described for pyrazine acrylic acid arotinoid, 14 d. Heterocyclic arotinoids derived from central-region dihalogenated pyrazine scaffolds have been synthesized by consecutive halogen and/or position-selective palladium-catalyzed cross-coupling reactions. Pyrazines were further functionalized as alkyl ethers or methylamines prior to the last Pd-catalyzed reactions. Transient transactivation studies with the retinoic acid receptor (RAR) alpha, beta, and gamma subtypes and with retinoid X receptor (RXR) alpha revealed distinct agonist, antagonist, and inverse agonist activities for these compounds. Of interest are the RARalpha,beta-selective inverse agonists with pyrazine acrylic acid structures, in particular 14 c, which is RARbeta-selective, and 14 d, a pan-RAR/RXR inverse agonist with more affinity for the RAR subtypes that enhance the interaction of RAR with cognate corepressors.

Dates and versions

inserm-00383337 , version 1 (12-05-2009)

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Cite

José García, Harshal Khanwalkar, Raquel Pereira, Cathie Erb, Johannes J. Voegel, et al.. Pyrazine arotinoids with inverse agonist activities on the retinoid and rexinoid receptors.. ChemBioChem, 2009, 10 (7), pp.1252-9. ⟨10.1002/cbic.200900030⟩. ⟨inserm-00383337⟩
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