Abstract
RXR partial agonist NEt-4IB (2a, 6-[ethyl-(4-isobutoxy-3-isopropylphenyl)amino]pyridine-3-carboxylic acid: EC50 = 169 nM, Emax = 55%) showed a blood concentration higher than its Emax after single oral administration at 30 mg/kg to mice, and repeated oral administration at 10 mg/kg/day to KK-Ay mice afforded antitype 2 diabetes activity without the side effects caused by RXR full agonists. However, RXR full agonist NEt-3IB (1a), in which the isobutoxy and isopropyl groups of 2a are interchanged, gave a much lower blood concentration than 2a. Here we used positron emission tomography (PET) with tracers [11C]1a, [11C]2a and fluorinated derivatives [18F]1b, [18F]2b, which have longer half-lives, to examine the reason why 1a and 2a exhibited significantly different blood concentrations. As a result, the reason for the high blood concentration of 2a after oral administration was found to be linked to higher intestinal absorbability together with lower biliary excretion, compared with 1a.
Original language | English |
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Pages (from-to) | 334-338 |
Number of pages | 5 |
Journal | ACS Medicinal Chemistry Letters |
Volume | 6 |
Issue number | 3 |
DOIs | |
Publication status | Published - Mar 12 2015 |
Keywords
- Nuclear receptors
- PET imaging
- RXR
- pharmacokinetics
ASJC Scopus subject areas
- Biochemistry
- Drug Discovery
- Organic Chemistry