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
N1 - Funding Information:
This work was partially supported by The Tokyo Biochemical Research Foundation (TBRF) (to H.K.).
Funding Information:
This work was partially supported by The Tokyo Biochemical Research Foundation (TBRF) (to H.K.).The authors are grateful to the Division of Instrumental Analysis, Okayama University for the NMR and MS measurements.
Publisher Copyright:
© 2019 Elsevier Ltd
PY - 2019/8/1
Y1 - 2019/8/1
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 - RXR
KW - Rexinoid
KW - Teratogenicity
KW - Zebrafish
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U2 - 10.1016/j.bmcl.2019.05.050
DO - 10.1016/j.bmcl.2019.05.050
M3 - Article
C2 - 31160175
AN - SCOPUS:85066309662
VL - 29
SP - 1891
EP - 1894
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
SN - 0960-894X
IS - 15
ER -