PMID- 20656484
OWN - NLM
STAT- MEDLINE
DCOM- 20101206
LR  - 20100816
IS  - 1464-3405 (Electronic)
IS  - 0960-894X (Linking)
VI  - 20
IP  - 17
DP  - 2010 Sep 1
TI  - Modification at the acidic domain of RXR agonists has little effect on permissive 
      RXR-heterodimer activation.
PG  - 5139-42
LID - 10.1016/j.bmcl.2010.07.012 [doi]
AB  - Retinoid X receptors (RXRs) function as homo- or heterodimers with other nuclear 
      receptors, such as peroxisome proliferator-activated receptors (PPARs), which are 
      targets for treatment of hyperlipidemia and type 2 diabetes, or liver X receptors 
      (LXRs), which are involved in glucose/lipid metabolism. PPAR/RXR or LXR/RXR are 
      known as permissive RXR-heterodimers because they are activated by RXR agonists 
      alone. Interestingly, the pattern of RXR-heterodimer activation is different 
      depending on the RXR agonist structure, but the structure-activity relationship 
      has not been reported. Here we show that modification or replacement of the 
      carboxyl group in the acidic domain of RXR agonists has little or no effect on 
      permissive RXR-heterodimer activation. Phosphonic acid (9), tetrazole (10), and 
      hydroxamic acid (12) analogues were synthesized from the common bromo 
      intermediate 7. Except for 9, these compounds showed RXR full-agonistic 
      activities in the concentration range of 1-10 microM. The order of agonistic 
      activity toward both PPARgamma/RXRalpha and LXRalpha/RXRalpha was the same as it 
      was for RXR, that is, 11>10>12. These results should be useful for the 
      development of RXR agonists with improved bioavailability.
CI  - Copyright 2010 Elsevier Ltd. All rights reserved.
FAU - Fujii, Shuji
AU  - Fujii S
AD  - Division of Pharmaceutical Sciences, Okayama University, Graduate School of 
      Medicine, Dentistry and Pharmaceutical Sciences, Tsushima-Naka, Okayama, Japan.
FAU - Ohsawa, Fuminori
AU  - Ohsawa F
FAU - Yamada, Shoya
AU  - Yamada S
FAU - Shinozaki, Ryosuke
AU  - Shinozaki R
FAU - Fukai, Ryosuke
AU  - Fukai R
FAU - Makishima, Makoto
AU  - Makishima M
FAU - Enomoto, Shuichi
AU  - Enomoto S
FAU - Tai, Akihiro
AU  - Tai A
FAU - Kakuta, Hiroki
AU  - Kakuta H
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100708
PL  - England
TA  - Bioorg Med Chem Lett
JT  - Bioorganic & medicinal chemistry letters
JID - 9107377
RN  - 0 (Retinoid X Receptors)
SB  - IM
MH  - Dimerization
MH  - Dose-Response Relationship, Drug
MH  - Models, Molecular
MH  - Retinoid X Receptors/*agonists/chemistry/genetics/metabolism
MH  - Transcriptional Activation
EDAT- 2010/07/27 06:00
MHDA- 2010/12/14 06:00
CRDT- 2010/07/27 06:00
PHST- 2010/05/23 00:00 [received]
PHST- 2010/06/25 00:00 [revised]
PHST- 2010/07/06 00:00 [accepted]
PHST- 2010/07/27 06:00 [entrez]
PHST- 2010/07/27 06:00 [pubmed]
PHST- 2010/12/14 06:00 [medline]
AID - S0960-894X(10)00968-6 [pii]
AID - 10.1016/j.bmcl.2010.07.012 [doi]
PST - ppublish
SO  - Bioorg Med Chem Lett. 2010 Sep 1;20(17):5139-42. doi: 10.1016/j.bmcl.2010.07.012. 
      Epub 2010 Jul 8.