Discovery of novel pyridinones as MGAT2 inhibitors for the treatment of metabolic disorders.
Bioorg Med Chem Lett
; 91: 129362, 2023 07 15.
Article
in En
| MEDLINE
| ID: mdl-37295614
ABSTRACT
Inhibition of monoacylglycerol transferase 2 (MGAT2) has recently emerged as a potential therapeutic strategy for the treatment of metabolic diseases such as obesity, diabetes and non-alcoholic steatohepatitis (NASH). Metabolism studies with our clinical lead (1) suggested variability in in vitro glucuronidation rates in liver microsomes across species, which made projection of human doses challenging. In addition, the observation of deconjugation of the C3-C4 double bond in the dihydropyridinone ring of 1 in solution had the potential to complicate its clinical development. This report describes our lead optimization efforts in a novel pyridinone series, exemplified by compound 33, which successfully addressed both of these potential issues.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Monoglycerides
/
Metabolic Diseases
Limits:
Humans
Language:
En
Journal:
Bioorg Med Chem Lett
Journal subject:
BIOQUIMICA
/
QUIMICA
Year:
2023
Document type:
Article
Affiliation country:
Estados Unidos