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Identification, synthesis, and biological evaluation of the metabolites of 3-amino-6-(3'-aminopropyl)-5H-indeno[1,2-c]isoquinoline-5,11-(6H)dione (AM6-36), a promising rexinoid lead compound for the development of cancer chemotherapeutic and chemopreventive agents.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2012 Jun 28; Vol. 55 (12), pp. 5965-81. Date of Electronic Publication: 2012 Jun 19. - Publication Year :
- 2012
-
Abstract
- Activation of the retinoid X receptor (RXR), which is involved in cell proliferation, differentiation, and apoptosis, is a strategy for cancer chemotherapy and chemoprevention, and 3-amino-6-(3'-aminopropyl)-5H-indeno[1,2-c]isoquinoline-5,11-(6H)dione (AM6-36) (3) is among the few RXR ligands known. The presently reported studies of 3 include its binding to human plasma proteins, metabolic stability using human liver microsomes, metabolism by human liver microsomes and hepatocytes, and in vivo disposition in rat serum, liver, and mammary tissue. Compound 3 was 75% bound to human plasma proteins, and its metabolic stability was much greater than propranolol. One phase I metabolite was formed by human liver microsomes, seven phase I and II metabolites were formed by human hepatocytes, and five metabolites were detected in rat serum and liver after oral administration. The putative metabolites predicted using LC-MS-MS were synthesized to confirm their structures and to provide sufficient material for investigation of induction of RXRE transcriptional activity and inhibition of NFκB.
- Subjects :
- Animals
Anticarcinogenic Agents chemistry
Anticarcinogenic Agents metabolism
Apoptosis drug effects
Cell Line, Tumor
Chemistry Techniques, Synthetic
Drug Stability
Female
Humans
Indenes chemistry
Indenes metabolism
Isoquinolines chemistry
Isoquinolines metabolism
Ligands
Microsomes, Liver metabolism
Rats
Response Elements drug effects
Retinoid X Receptors genetics
Transcription, Genetic drug effects
Anticarcinogenic Agents chemical synthesis
Anticarcinogenic Agents pharmacology
Drug Discovery
Indenes chemical synthesis
Indenes pharmacology
Isoquinolines chemical synthesis
Isoquinolines pharmacology
Retinoid X Receptors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 55
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 22712432
- Full Text :
- https://doi.org/10.1021/jm3006806