RXR Partial Agonist Produced by Side Chain Repositioning of Alkoxy RXR Full Agonist Retains Antitype 2 Diabetes Activity without the Adverse Effects

Abstract

We previously reported RXR partial agonist CBt-PMN (1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5-carboxylic acid: 5, EC50 = 143 nM, Emax = 75%), which showed a potent glucose-lowering effect without causing serious adverse effects. However, it remains important to elucidate the structural requirements for RXR efficacy and the glucose-lowering effect because RXR-permissive heterodimers such as PPAR/RXR or LXR/RXR are reported to be activated differently depending upon the chemical structure of RXR agonists. In this work, we show that an RXR partial agonist, NEt-4IB (6-[ethyl-(4-isobutoxy-3-isopropylphenyl)amino]pyridine-3-carboxylic acid: 8b, EC50 = 169 nM, Emax = 55%), can be obtained simply by repositioning the side chains (interchanging the isobutoxy and isopropoxy groups) at the hydrophobic moiety of the RXR full agonist NEt-3IB (6-[ethyl-(3-isobutoxy-4-isopropylphenyl)amino]pyridine-3-carboxylic acid: 7b, EC50 = 19 nM). NEt-4IB (8b) showed antitype 2 diabetes activity without the above side effects upon repeated oral administration to mice at 10 mg/kg/day, similarly to 5.

Effect of a retinoid X receptor partial agonist on airway inflammation and hyperresponsiveness in a murine model of asthma

“…However, RXR full agonists are associated with strong adverse events, including the elevation of blood triglycerides, hepatomegaly and hypothyroidism [12, 13]. Accordingly, we developed a novel RXR partial agonist that displays no significant adverse events even with 28 consecutive days’ administration compared with full agonists [14]. In this study, elevations of TG levels and liver size were not recognized in OVA/OVA/NEt-4IB mice compared with OVA/OVA/vehicle mice.…”

“…The novel RXR partial agonist NEt-4IB has a maximum 55% RXR efficacy compared with full agonists in a luciferase reporter gene assay, and 28 consecutive days’ administration of NEt-4IB resulted in no significant adverse events [14]. Furthermore, we have investigated the pharmacokinetics of NEt-4IB in vivo by positron emission tomography (PET) and revealed an increase in radioactivity in PET imaging of the lung [15].…”

A review of the molecular design and biological activities of RXR agonists

“…Compound 39 showed 50% to 60% activation toward RXRα,β, and γ with dose‐dependency and produced partial inhibition of the activity of 2 , confirming its properties as a partial agonist. In addition, 39 induced permissive activation of LXLα/RXRα and PPARγ/RXRα heterodimers . Molecule 39 (EC 50 = 169 nM) has antitype 2 diabetes activity with reduced side effects compared to full RXR agonists in animal models and gave a higher blood concentration than full agonist 33 , after oral administration .…”

“…Inspired by the partial RXR agonist CBt‐PMN ( 38 , Figure ), a compound reported to significantly lower glucose levels, Kawata et al sought to develop partial RXR agonists. The group synthesized the RXR partial agonist NEt‐ 4IB (39) by exchanging the isobutyl and isopropyl groups at the lipophilic moiety of the RXR full agonist 33 .…”

Retinoid X Receptor Antagonists

“…To reduce the lipid solubility of existing RXR agonists, the RXR full agonist NEt-3IB ( 37 , EC 50 = 19 nM), which has an isobutoxy group at a hydrophobic site, was designed [27,82]. The para position to the isobutoxy group on the benzene ring is electron-rich because this position is also at the ortho position relative to the nitrogen atom of the amino linking group.…”