Abstract
Several retinoid X receptor (RXR) ligands (rexinoids), such as bexarotene (1), exhibit teratogenicity, which is a serious impediment to their clinical application. We considered that rexinoids with a lower level of maximal RXR transcription activation (i.e., partial agonists) and lower lipid solubility might show weaker adverse side effects. Based on this idea, we modified our previously reported pentamethyltetralin-type RXR partial agonists 5 and 6 to reduce their lipophilicity. Here, we report a new RXR partial agonist, 3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (8, CATF-PMN), which showed greatly reduced teratogenicity in zebrafish embryos.
| Original language | English |
|---|---|
| Journal | Bioorganic and Medicinal Chemistry Letters |
| DOIs | |
| Publication status | Published - Jan 1 2019 |
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Keywords
- Nuclear receptor
- Rexinoid
- RXR
- Teratogenicity
- Zebrafish
ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
- Molecular Biology
- Pharmaceutical Science
- Drug Discovery
- Clinical Biochemistry
- Organic Chemistry
Cite this
3H-Imidazo[4,5-b]pyridine-6-carboxylic acid derivatives as rexinoids with reduced teratogenicity. / Takamura, Yuta; Takahashi, Manami; Nishii, Midori; Shibahara, Osamu; Watanabe, Masaki; Fujihara, Michiko; Kakuta, Hiroki.
In: Bioorganic and Medicinal Chemistry Letters, 01.01.2019.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid derivatives as rexinoids with reduced teratogenicity
AU - Takamura, Yuta
AU - Takahashi, Manami
AU - Nishii, Midori
AU - Shibahara, Osamu
AU - Watanabe, Masaki
AU - Fujihara, Michiko
AU - Kakuta, Hiroki
PY - 2019/1/1
Y1 - 2019/1/1
N2 - Several retinoid X receptor (RXR) ligands (rexinoids), such as bexarotene (1), exhibit teratogenicity, which is a serious impediment to their clinical application. We considered that rexinoids with a lower level of maximal RXR transcription activation (i.e., partial agonists) and lower lipid solubility might show weaker adverse side effects. Based on this idea, we modified our previously reported pentamethyltetralin-type RXR partial agonists 5 and 6 to reduce their lipophilicity. Here, we report a new RXR partial agonist, 3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (8, CATF-PMN), which showed greatly reduced teratogenicity in zebrafish embryos.
AB - Several retinoid X receptor (RXR) ligands (rexinoids), such as bexarotene (1), exhibit teratogenicity, which is a serious impediment to their clinical application. We considered that rexinoids with a lower level of maximal RXR transcription activation (i.e., partial agonists) and lower lipid solubility might show weaker adverse side effects. Based on this idea, we modified our previously reported pentamethyltetralin-type RXR partial agonists 5 and 6 to reduce their lipophilicity. Here, we report a new RXR partial agonist, 3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (8, CATF-PMN), which showed greatly reduced teratogenicity in zebrafish embryos.
KW - Nuclear receptor
KW - Rexinoid
KW - RXR
KW - Teratogenicity
KW - Zebrafish
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UR - http://www.scopus.com/inward/citedby.url?scp=85066309662&partnerID=8YFLogxK
U2 - 10.1016/j.bmcl.2019.05.050
DO - 10.1016/j.bmcl.2019.05.050
M3 - Article
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
SN - 0960-894X
ER -