Oxaprozin Analogues as Selective RXR Agonists with Superior Properties and Pharmacokinetics.
Animals
Binding Sites
Cell Survival
/ drug effects
Crystallography, X-Ray
Half-Life
Humans
Ligands
Mice
Microsomes
/ metabolism
Molecular Dynamics Simulation
Oxaprozin
/ analogs & derivatives
Protein Isoforms
/ agonists
Pyrazoles
/ chemistry
Rats
Retinoid X Receptors
/ agonists
Structure-Activity Relationship
Journal
Journal of medicinal chemistry
ISSN: 1520-4804
Titre abrégé: J Med Chem
Pays: United States
ID NLM: 9716531
Informations de publication
Date de publication:
22 04 2021
22 04 2021
Historique:
pubmed:
2
4
2021
medline:
16
6
2021
entrez:
1
4
2021
Statut:
ppublish
Résumé
The retinoid X receptors (RXR) are ligand-activated transcription factors involved in multiple regulatory networks as universal heterodimer partners for nuclear receptors. Despite their high therapeutic potential in many pathologies, targeting of RXR has only been exploited in cancer treatment as the currently available RXR agonists suffer from exceptional lipophilicity, poor pharmacokinetics (PK), and adverse effects. Aiming to overcome the limitations and to provide improved RXR ligands, we developed a new potent RXR ligand chemotype based on the nonsteroidal anti-inflammatory drug oxaprozin. Systematic structure-activity relationship analysis enabled structural optimization toward low nanomolar potency similar to the well-established rexinoids. Cocrystal structures of the most active derivatives demonstrated orthosteric binding, and
Identifiants
pubmed: 33793232
doi: 10.1021/acs.jmedchem.1c00235
doi:
Substances chimiques
Ligands
0
Protein Isoforms
0
Pyrazoles
0
Retinoid X Receptors
0
Oxaprozin
MHJ80W9LRB
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM