Replacing alkyl sulfonamide with aromatic sulfonamide in sulfonamide-type RXR agonists favors switch towards antagonist activity

Morishita, Ken Ichi; Yakushiji, Nobumasa; Ohsawa, Fuminori; Takamatsu, Kayo; Matsuura, Nobuo; Makishima, Makoto; Kawahata, Masatoshi; Yamaguchi, Kentaro; Tai, Akihiro; Sasaki, Kenji; Kakuta, Hiroki

doi:10.1016/j.bmcl.2008.11.086

Cited by 20 publications

(11 citation statements)

References 17 publications

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“…6-[ N -ethyl- N -(3-isopropoxy-4-isopropylphenyl)-amino] nicotinic acid (NEt-3IP), 6-[ N - 4 -(trifluoromethyl) benzenesulfonyl- N -(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl) amino] nicotinic acid (NS-4TF), and 3′-((2-fluoro-4-(trifluoromethyl) benzamido) methyl)-4′-propoxybiphenyl-4-carboxylic acid (JKPL-85) were synthesized at Okayama University [24, 25]. NEt-3IP and pioglitazone (Actos; Takeda Pharmaceutics, Osaka, Japan) were suspended in 0.5% carboxymethylcellulose solution.…”

Section: Methodsmentioning

confidence: 99%

Involvement of the Retinoid X Receptor Ligand in the Anti-Inflammatory Effect Induced by Peroxisome Proliferator-Activated Receptor Agonist In Vivo

et al. 2011

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Peroxisome proliferator-activated receptor γ (PPARγ) forms a heterodimeric DNA-binding complex with retinoid X receptors (RXRs). It has been reported that the effect of the PPAR agonist is reduced in hepatocyte RXR-deficient mice. Therefore, it is suggested that the endogenous RXR ligand is involved in the PPARγ agonist-induced anti-inflammatory effect. However, the participation of the RXR ligand in the PPARγ-induced anti-inflammatory effect is unknown. Here, we investigated the influence of RXR antagonist on the anti-inflammatory effect of PPARγ agonist pioglitazone in carrageenan test. In addition, we also examined the influence of PPAR antagonist on the anti-inflammatory effect induced by RXR agonist NEt-3IP. The RXR antagonist suppressed the antiedema effect of PPARγ agonist. In addition, the anti-inflammatory effect of RXR agonist was suppressed by PPARγ antagonist. PPARγ agonist-induced anti-inflammatory effects were reversed by the RXR antagonist. Thus, we showed that the endogenous RXR ligand might contribute to the PPARγ agonist-induced anti-inflammatory effect.

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Section: Methodsmentioning

confidence: 99%

Involvement of the Retinoid X Receptor Ligand in the Anti-Inflammatory Effect Induced by Peroxisome Proliferator-Activated Receptor Agonist In Vivo

et al. 2011

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“…Sulfonamides 12.5a,b showed IC 50 values below 10 μM. Aromatic sulfonamides of the same skeleton display greater antagonistic activities [106]. The good pharmacokinetic profile of 12.5a in rats was considered to be appropriate for the treatment of diabetes and obesity [104,105].…”

Section: Rxr Antagonistsmentioning

confidence: 98%

“…Preferential RXR agonism relative to PA024 (11.3a, which has been characterized as an agonist with greater potency with RXR / than with RXR ) was described for analogues 13.1 that feature the less lipophilic sulfonamide functional group [115]. Replacing alkylsulfonamides (13.1a) by arylsulfonamides (13.1b) led to moderate RXR -selective antagonists [106].…”

Section: Rxr Subtype-selective Ligandsmentioning

confidence: 98%

Retinoid Receptors and Therapeutic Applications of RAR/RXR Modulators

Maire¹,

Álvarez²,

Shankaranarayanan³

et al. 2012

CTMC

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Retinoic acid receptors (RARs) are ligand-controlled transcription factors that function as heterodimers with retinoid X receptors (RXRs) to regulate cell growth, differentiation, survival and death. Due to their regulatory potential, these nuclear receptors (NRs) are major drug targets for a variety of pathologies, including cancer and metabolic diseases. A large amount of RAR- and RXR-selective ligands, ranging from (partial) agonists to antagonists and inverse agonists, have been designed and the corresponding structural and functional analyses have provided deep insight into the molecular basis of ligand action. Ligands regulate, via allosteric conformational changes, the ability of these NRs to interact with different sets of coregulators, which in turn recruit enzymatically active complexes/machineries. Here, we describe strategies in the design of selective RXR and RAR modulators and review the structural mechanisms by which the diverse pharmacological classes of compounds modulate receptor functions. Finally, we discuss the perspectives for retinoid- and rexinoid-based therapies.

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“…Although some subtype-preferential agonists and antagonists have been reported [27,28,29], their selectivities are not sufficient to allow their use as pharmacological tools [30]. The main reason for the difficulty in developing highly selective RXR ligands may be that the amino acid residues of helices (H) 3, 5, 7, and 11, and the β-turn, which form the ligand-binding pocket, are highly conserved in RXRα, β, and γ.…”

Section: The Rxrsmentioning

confidence: 99%

Retinoid X Receptor Antagonists

Watanabe

Kakuta

2018

IJMS

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Retinoid X receptor (RXR) antagonists are not only useful as chemical tools for biological research, but are also candidate drugs for the treatment of various diseases, including diabetes and allergies, although no RXR antagonist has yet been approved for clinical use. In this review, we present a brief overview of RXR structure, function, and target genes, and describe currently available RXR antagonists, their structural classification, and their evaluation, focusing on the latest research.

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Replacing alkyl sulfonamide with aromatic sulfonamide in sulfonamide-type RXR agonists favors switch towards antagonist activity

Cited by 20 publications

References 17 publications

Involvement of the Retinoid X Receptor Ligand in the Anti-Inflammatory Effect Induced by Peroxisome Proliferator-Activated Receptor Agonist In Vivo

Involvement of the Retinoid X Receptor Ligand in the Anti-Inflammatory Effect Induced by Peroxisome Proliferator-Activated Receptor Agonist In Vivo

Retinoid Receptors and Therapeutic Applications of RAR/RXR Modulators

Retinoid X Receptor Antagonists

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