PMID- 30783504
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20231006
IS  - 1948-5875 (Print)
IS  - 1948-5875 (Electronic)
IS  - 1948-5875 (Linking)
VI  - 10
IP  - 2
DP  - 2019 Feb 14
TI  - Computer-Assisted Discovery and Structural Optimization of a Novel Retinoid X 
      Receptor Agonist Chemotype.
PG  - 203-208
LID - 10.1021/acsmedchemlett.8b00551 [doi]
AB  - As universal heterodimer partners of many nuclear receptors, the retinoid X 
      receptors (RXRs) constitute key transcription factors. They regulate cell 
      proliferation, differentiation, inflammation, and metabolic homeostasis and have 
      recently been proposed as potential drug targets for neurodegenerative and 
      inflammatory diseases. Owing to the hydrophobic nature of RXR ligand binding 
      sites, available synthetic RXR ligands are lipophilic, and their structural 
      diversity is limited. Here, we disclose the computer-assisted discovery of a 
      novel RXR agonist chemotype and its systematic optimization toward potent RXR 
      modulators. We have developed a nanomolar RXR agonist with high selectivity among 
      nuclear receptors and superior physicochemical properties compared to classical 
      rexinoids that appears suitable for in vivo applications and as lead for future 
      RXR-targeting medicinal chemistry.
FAU - Heitel, Pascal
AU  - Heitel P
AD  - Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 
      Max-von-Laue-Str. 9, 60438 Frankfurt, Germany.
FAU - Gellrich, Leonie
AU  - Gellrich L
AD  - Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 
      Max-von-Laue-Str. 9, 60438 Frankfurt, Germany.
FAU - Kalinowsky, Lena
AU  - Kalinowsky L
AD  - Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 
      Max-von-Laue-Str. 9, 60438 Frankfurt, Germany.
FAU - Heering, Jan
AU  - Heering J
AD  - Project Group Translational Medicine and Pharmacology TMP, Fraunhofer Institute 
      for Molecular Biology and Applied Ecology IME, Theodor-Stern-Kai 7, D-60596 
      Frankfurt, Germany.
FAU - Kaiser, Astrid
AU  - Kaiser A
AD  - Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 
      Max-von-Laue-Str. 9, 60438 Frankfurt, Germany.
FAU - Ohrndorf, Julia
AU  - Ohrndorf J
AD  - Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 
      Max-von-Laue-Str. 9, 60438 Frankfurt, Germany.
FAU - Proschak, Ewgenij
AU  - Proschak E
AD  - Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 
      Max-von-Laue-Str. 9, 60438 Frankfurt, Germany.
FAU - Merk, Daniel
AU  - Merk D
AD  - Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 
      Max-von-Laue-Str. 9, 60438 Frankfurt, Germany.
LA  - eng
PT  - Journal Article
DEP - 20190104
PL  - United States
TA  - ACS Med Chem Lett
JT  - ACS medicinal chemistry letters
JID - 101521073
PMC - PMC6378677
COIS- The authors declare no competing financial interest.
EDAT- 2019/02/21 06:00
MHDA- 2019/02/21 06:01
PMCR- 2020/02/14
CRDT- 2019/02/21 06:00
PHST- 2018/11/16 00:00 [received]
PHST- 2018/12/27 00:00 [accepted]
PHST- 2019/02/21 06:00 [entrez]
PHST- 2019/02/21 06:00 [pubmed]
PHST- 2019/02/21 06:01 [medline]
PHST- 2020/02/14 00:00 [pmc-release]
AID - 10.1021/acsmedchemlett.8b00551 [doi]
PST - epublish
SO  - ACS Med Chem Lett. 2019 Jan 4;10(2):203-208. doi: 10.1021/acsmedchemlett.8b00551. 
      eCollection 2019 Feb 14.