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

Abstract

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) α, β, and γ subtypes and with retinoid X receptor (RXR) a revealed distinct agonist, antagonist, and inverse agonist activities for these compounds. Of interest are the RARα,β-selective inverse agonists with pyrazine acrylic acid structures, in particular 14c, which is RARβ-selective, and 14d, a pan-RAR/RXR inverse agonist with more affinity for the RAR subtypes that enhance the interaction of RAR with cognate corepressors. © 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.