Synthesis and structure–activity relationship of novel RXR antagonists: Orally active anti-diabetic and anti-obesity agents

Sakaki, Junichi; Kishida, Masashi; Konishi, Kenichi; Gunji, Hiroki; Toyao, Atsushi; Matsumoto, Yuki; Kanazawa, Takanori; Uchiyama, Hidefumi; Fukaya, Hiroaki; Mitani, Hironobu; Arai, Yukiko; Kimura, Masaaki

doi:10.1016/j.bmcl.2007.06.080

Cited by 23 publications

(41 citation statements)

References 3 publications

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“…[12] Heteroaromatic rings have been included as central retinoid linkers less frequently. [14,[16][17][18][19] We therefore set out to design, synthesize and assess the ligand binding of a collection of retinoids that have a pyrazine heterocycle as a central connecting unit. To meet the structural requirements for RAR or RXR selectivity, we focused on two series of positional isomers that are derived from 2,3,6-and 2,3,5-trisubstituted pyrazines (Scheme 1).…”

Section: Introductionmentioning

confidence: 99%

Pyrazine Arotinoids with Inverse Agonist Activities on the Retinoid and Rexinoid Receptors

García¹,

Khanwalkar²,

Pereira³

et al. 2009

ChemBioChem

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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.

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Section: Introductionmentioning

confidence: 99%

Pyrazine Arotinoids with Inverse Agonist Activities on the Retinoid and Rexinoid Receptors

García¹,

Khanwalkar²,

Pereira³

et al. 2009

ChemBioChem

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“…However, undesirable side effects such as hypertriglyceridemia and suppression of the thyroid hormone axis also exist (6). Currently, there have been increasing numbers of reports on RXR antagonists, which are found to decrease body weight, plasma glucose, and insulin levels, while exhibiting few effects on food intake in vivo (17,18).…”

mentioning

confidence: 99%

Danthron Functions as a Retinoic X Receptor Antagonist by Stabilizing Tetramers of the Receptor

Zhang

Zhou

et al. 2011

Journal of Biological Chemistry

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Retinoic X receptor (RXR) is a promising target for drug discovery against cancer and metabolic syndromes. Here, we identified a specific RXR␣ antagonist, danthron, from the traditional Chinese medicine rhubarb. Danthron repressed all tested RXR␣-involved response element transcription, including the RXRE, PPRE, FXRE, and LXRE. Results from native PAGE and isothermal titration calorimetry (ITC)-based assays indicated that danthron bound to the tetrameric RXR␣-LBD in a specific stoichimetric ratio, and such a binding could influence the corepressor SMRT affinity to the receptor. Additionally, a unique tetrameric structure of the apo-RXR␣ ligand-binding domain (LBD) was determined, which exhibited a larger tetramer interface and different ligand-binding pocket size compared with the one previously reported. Together with the biochemical and biophysical results, the determined crystal structure of danthron-soaked RXR␣-LBD suggested a new mechanism for danthron antagonism to tetrameric RXR␣. Moreover, the in vivo efficient improvement of insulin sensitivity by danthron was observed in diet-induced obese (DIO) mice. Thus, our findings were expected to supply new insights into the structural basis of RXR␣ antagonist for its further potential therapeutic application.

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“…The thiazepine HX630 5.1b and azepine HX640 5.1c derivatives are also retinoid synergists more potent than HX600 5.1a [71]. Sulfonamides 5.2a,b and nitriles 5.3b,c [72,73] are RXR antagonists, whereas the nitroderivative HX531 5.3a is a partial antagonist. The nitrile analogue with o-fluorobenzoic acid 5.3c was also characterized as RXR-RXR homodimer antagonist, although additional fluorine substituents at the same ring decreased this activity [73].…”

Section: Structure-based Design Of Rexinoid Modulatorsmentioning

confidence: 97%

Advances in drug design with RXR modulators

Vaz

Lera

2012

Expert Opinion on Drug Discovery

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Synthesis and structure–activity relationship of novel RXR antagonists: Orally active anti-diabetic and anti-obesity agents

Cited by 23 publications

References 3 publications

Pyrazine Arotinoids with Inverse Agonist Activities on the Retinoid and Rexinoid Receptors

Pyrazine Arotinoids with Inverse Agonist Activities on the Retinoid and Rexinoid Receptors

Danthron Functions as a Retinoic X Receptor Antagonist by Stabilizing Tetramers of the Receptor

Advances in drug design with RXR modulators

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